Pharmacy Practice News - October 2009 - Digital Edition

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Volume 36 • Number 10 • October 2009 ❃

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More Evidence Supports in this issue Front Key Role for Pharmacists Up Capsules On Emergency Care Team Boston—Having a pharmacist in the emergency department (ED) can significantly reduce medication errors and improve patient safety in that often-chaotic setting, according to two new studies presented this month at the annual meeting of the American College of Emergency Physicians (ACEP).

The investigators showed that they were able to prevent hundreds of errors caused by underdosing, overdosing, wrong-drug administration and other mishaps that could have severely compromised patient safety in the ED. “These researchers have done an amazing job with a very difficult task: documenting the value that emergency pharmacists bring as members of the multidisciplinary team in the ED,” said Nicole M. Acquisto, PharmD, emergency medicine clinical pharmacy specialist at the University of Rochester Medical Center, in New York.

The studies, conducted with grants from the

•

see ED CARE, page 38

Pharmacists help prevent potentially lethal QTc prolongation

3

Honoring pharmacy’s fallen on Veterans Day

10

Clinical

Hem/Onc Pharmacy Is it time to push first-line imatinib dose for CML?

16

Roundtable Pain experts debate FDA’s proposals to combat acetaminophen toxicity

26

Policy

Finance ‘Never events’ rules generate paltry savings

34

Education Pharmacy school shines in oncology drug research

Findings could help achieve earlier interventions, lower mortality in NICU Anaheim, Calif.—A new study has identified four main risk factors for the development of invasive candidiasis in critically ill infants.

The conditions, which included congenital heart disease and gastrointestinal (GI)/abdominal surgery, should be seen as a warning sign that early, preventive therapy with antifungal agents may be warranted, according to lead author Mike K. Wang, PharmD, a resource pharmacist at Long Beach Memorial Hospital in Long Beach, Calif.

Dr. Wang and his colleagues presented the results of the study at the annual meeting of the American College of Clinical Pharmacy (ACCP).

•

see CANDIDIASIS, page 24

After Hyponatremia Deaths, Stronger Interventions Urged

Pharmacy Heritage

Operations & Mgmt

Study IDs Risk Factors For Invasive Candidiasis

Pharmacist error cited in one case

D

espite years of warnings and recommendations, postoperative hyponatremia has struck again, taking the lives of two 6-year-old children, both of them previously healthy and undergoing routine surgery at two separate health systems.

The deaths, reported by the Institute for Safe Medication Practices (ISMP), prompted urgent calls from pharmacists and physicians for hospitals to reassess their protocols, materials management, order sets and other strategies to avoid these tragic, unintentional deaths.

One of the cases involved a postoperative order including IV fluids of

•

36

see HYPONATREMIA DEATHS, page 31

Technology

Robotics Drug carousel implementation tips

48

Educational Review Post-op Ileus: Prevention and Management See www.pharmacypracticenews.com

The Road to Compliance: Implementing New Standards for IV Drug Preparation 6

Antibiotic Stewardship Pays Off Quality of daptomycin prescribing improved via restrictive, pharmacist-coordinated protocol Anaheim, Calif.—Inappropriate daptomycin orders declined significantly at St. Luke’s Episcopal Hospital in Houston, after a restrictive protocol was launched earlier this year as part of a collaborative antimicrobial stewardship program, according to pharmacist-researchers who presented the results of a study at the American College of Clinical Pharmacy (ACCP) meeting in October.

The protocol, developed by a team that included infectious disease (ID) pharmacists and physicians, limited use of the novel cyclic lipopeptide antibiotic to ID physicians and defined recommended dosages for various indications, including infections caused by methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

•

see STEWARDSHIP, page 12

The Book Page Teddy Bear Book: Pediatric Injectable Drugs: 8th Edition Stephanie J. Phelps; Emily B. Hak; Catherine M. Crill See page

41

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Up Front 3

Pharmacy Practice News • October 2009

Capsules In Brief/ACCP Annual Meeting

surf

A Team Approach to QTc Prolongation Pays Off

watch

OCTOBER 2009

The six most-viewed articles last month on pharmacypracticenews.com: 1. Antimicrobial Efficacy 2. Strong Medication Reconciliation Effort Lowers ADE Readmissions 3. Hospitals May Be Letting Crucial Drug Pricing Tool Rust 4. Closed-System Transfer Devices Lessen Worker Contamination—at a Cost 5. August 2009 - Digital Edition 6. Assessment Tools and Guidelines: Parenteral Nutrition Therapy Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

Your Letters

Dr. Worthen Worthy of Praise To the Editor:

I

just finished reading, with much pleasure, Dennis Worthen’s article, “How Hot Is Hot?” (August, page 36). Thanks for a very informative review/reminder of my pharmacognosy courses taught by Dr. “Hoot” Gibson at the University of Georgia College of Pharmacy in Athens (45 years ago!). In fact, I had forgotten the name of Wilbur L. Scoville, the pharmacist who devised the heat scale for peppers. I appreciate Dr. Worthen bringing it all back in such a wonderful article about Capsicum fastigiatum Blume, or cayenne pepper.

I will certainly make sure my students read this!

J. Wesley Krulic, PharmD Regional Coordinator and Clinical Assistant Professor The University of Georgia College of Pharmacy Office of Experiential Programs St. Joseph’s/Candler Health Systems Inc. Savannah, Georgia

ANAHEIM, CALIF.—The first study to ever document the effects of a pharmacistcoordinated, multidisciplinary telemonitoring and intervention program indicates that the approach can prevent potentially life-threatening drug-induced ventricular arrhythmias.

The telemonitoring system measures the QTC interval corrected for heart rate (QTc), a precursor for torsades de pointes (TdP). The arrhythmia can be caused by several drugs, including droperidol and haloperidol, both of which have black-box warnings on the side effect included in labeling.

In the study, the researchers evaluated 729 patients with QTc prolongation. Medical records were reviewed for baseline and daily QTc values, electrolyte status and impact of current medications. Physician contact after assessment was initiated for all QTc values greater than 450 ms.

Significant QTc prolongation was identified in 45 patients. In 23 of those patients, pharmacists notified the prescribing physicians that the heart-rhythm abnormality may have been drug-induced.

“We found that about half of the patients were on multiple QTc-prolonging medications,” said co-investigator Harminder Sikand, PharmD, clinical and residency director at Scripps Mercy Hospital. “We discontinued the medications in three of the patients and changed the medication for another three.” Overall, 25% of the patients had a treatment change due to the QTc monitoring process, Dr. Sikand noted.

Three patients had nonsustained ventricular tachycardia, but no patient developed cardiac arrest and no deaths were reported. “I’m not sure how much weight we can put on that [latter] outcome, as our numbers were small,” she said.

Hospitals considering launching such a telemonitoring program should be prepared for implementation hurdles. For example, “nursing compliance with QTc calculation and determining the etiology of QTc prolongation were quite challenging,” Dr. Sikand said.

She added that more research is needed before recommending widespread adoption of automated QTc notification systems.

“We really need to look at the efficacy of [this strategy] versus a manual calculation and reporting process. We also need a larger study to determine if such detailed monitoring benefits our patients.”

Dr. Sikand and lead author Ederlyn Dia, PharmD presented the results of the study at the American College of Clinical Pharmacy annual meeting.

—David Bronstein

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4 Clinical

Pharmacy Practice News • October 2009

Cardiology

Recorder Differentiates Between Syncope and Epilepsy Implantable ECG device can help nail down diagnosis, avert wrong medication therapy Barcelona, Spain—An implantable electrocardiogram (ECG) loop recorder helps to differentiate between patients whose brief loss of consciousness is due to syncope (fainting) or to epilepsy, according to a trial presented at the 2009 Congress of the European Society of Cardiology.

The study, called REVISE (Reveal in the Investigation of Syncope and Epilepsy), found that one in eight adult patients previously thought to be suffering from epilepsy, or in whom this diagnosis was in doubt, in fact had syncope as diagnosed by the implanted loop recorder. When these patients subsequently received a pacemaker, their fainting symptoms resolved.

Sanjiv Petkar, MD, from Castle Hill Hospital, in Kingston-upon-Hull, United Kingdom, told reporters at a press conference that previous studies have suggested that one in four people diagnosed with epilepsy do not, in fact, have the condition.

About 74,000 people in that country are taking antiepileptic medication they do not need, he said. “In our study, we found that nearly 60% of our population had been on antiepileptic drugs, including the newer anticonvulsants as well as the older ones, at some point.

Some of our patients had long-standing problems; one person had been thought to have had epilepsy for 26 years, when in fact that person had syncope.”

The misdiagnosis is very costly, Dr. Petkar said, in terms of both direct medical costs and indirect costs. In Britain, it is estimated that the direct medical costs of an epilepsy misdiagnosis is 29 million pounds (nearly $48

million USD), and the indirect costs, which include loss of employment, driving restrictions and even fetal developmental abnormalities that can occur when women of childbearing age take antiepileptic drugs, are estimated to be around 138 million pounds (nearly $203 million USD) annually.

Trial Detailed The REVISE trial, which was funded

by Medtronic, Inc., the maker of the device, included adult patients aged 18 years and older who experienced transient loss of consciousness and in whom a misdiagnosis of epilepsy was suspected, or whose diagnosis of epilepsy was doubted by neurologists with

median age was 39 years (range, 18-80), and median duration of symptoms was 96 months (range, 12-540). At enrollment, 24 patients (58.5%) had taken or were currently taking antiepileptic drugs; the mean number of these drugs was two, with some patients taking as many as four.

The loop recorder device recorded a heart rhythm at the time of fainting in 29 (70.7%) of the patients. Seven patients were found to have an abnormal heart rhythm; four had sinus arrest and three had atrioventricular block.

Six of these patients agreed to be implanted with a pacemaker and five remained asymptomatic over the following nine months.

“This is a small study and the findings need confirmation in a larger evaluation,” Dr. Petkar said. “We also need to raise awareness among medical professionals that syncope can present with abnormal movements and we obviously need closer cooperation between cardiologists and neurologists, so that we can help these patients.”

Pharmacist’s Perspective

‘In our study, we found that nearly 60% of our population had been on antiepileptic drugs, including the newer anticonvulsants as well as the older ones, at some point. Some of our patients had long-standing problems; one person had been thought to have had epilepsy for 26 years, when in fact that person had syncope.’

—Sanjiv Petkar, MD an interest in epilepsy. The patients had three or more fainting episodes in the 12 months before study entry. Additionally, they were required to have a normal, equivocal or nondiagnostic 12 lead ECG, 24-hour ECG, standard unprovoked electroencephalogram, and normal brain computed tomography or magnetic resonance imaging scans.

Overall, 41 patients (26 females, 15 males) received a loop recorder. Their

In four of the patients, the device recorded signals due to muscle shaking which were suggestive of tonic-clonic seizures. Two of these patients were started on antiepileptic medication, Dr. Petkar said.

Antiepileptic drugs were withdrawn in eight of the 24 patients who were taking them at the start of the study, and six of these patients remained asymptomatic afterward.

Commenting on this study for Pharmacy Practice News, Amy Seybert, PharmD, associate professor at the University of Pittsburgh School of Pharmacy, said the small size of the study was of concern and agreed that larger studies need to be done before the loop recorder can be considered the answer to the problem of diagnosing epilepsy versus syncope. “I fear that if we label folks as not having epilepsy and withdraw treatment when they actually do have epilepsy, this could be problematic. We really do need more studies.”

Dr. Seybert stressed that more collaboration between cardiologists and neurologists is needed. “If these two physician groups can come to a consensus on an individual basis and do what’s best for the patient, that’s the real key. This study brings light to that idea.”

—Fran Lowry

‘Breakthrough study’ at ESC Congress triggers excitement

New Oral Anticoagulant Rivals Warfarin in Atrial Fibrillation Patients Barcelona, Spain—A novel oral thrombin inhibitor, dabigatran etexilate, is more effective than warfarin in preventing stroke in patients with atrial fibrillation, according to a large, multicenter trial presented at the 2009 Congress of the European Society of Cardiology.

As shown in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant therapy) study, dabigatran (Boehringer Ingleheim), when given at the higher of two doses that were tested, reduced the risk for stroke by 34% and the risk for hemorrhagic stroke by 74% (P<0.001) in comparison with warfarin. When given at the lower of the two doses, dabigatran was associated with similar rates of

stroke as warfarin, but with significantly less major bleeding. RE-LY, which generated a lot of excitement at the Congress, was presented by its principal investigator, Stuart J. Connolly, MD, director of cardiology at McMaster University, Hamilton, Ontario, Canada and was published simultaneously online at www.nejm.org (DOI: 10.1056/NEJM0a0905561).

“RE-LY is a breakthrough study because it shows that dabigatran is not only safer and more effective than warfarin, but is also going to be much easier to use for patients,” Dr. Connolly told Pharmacy Practice News. “We have been looking for decades to find a replacement for warfarin, but nothing has been successful as an

oral blood thinner, until now.”

Dabigatran etexilate is a prodrug that is rapidly converted to dabigatran, a direct thrombin inhibitor. It has 6.5% bioavailability and is 80% excreted by the kidney, with a half-life of 12 to 17 hours.

The trial randomized 18,113 patients from 951 centers in 44 countries to dabigatran 110 mg (n=6,015 patients), dabigatran 150 mg (n=6,076 patients) or warfarin (n=6,022 patients). The primary outcome was systemic embolism or stroke, including hemorrhagic stroke. Over the median two-year follow-up, the rates of the primary outcome were 1.69% per year on warfarin versus 1.53% per year on dabigatran 110 mg (relative risk [RR] 0.91;

95% confidence interval [CI], 0.74-1.11; P<0.001 for noninferiority); and 1.11% per year on dabigatran 150 mg (RR, 0.66; 95% CI, 0.53-0.82; P<0.001 for superiority).

Rates of major hemorrhage were 3.36% per year on warfarin versus 2.71% on dabigatran 110 mg (P=0.003) and 3.36% on dabigatran 150 mg (P=0.31). Rates of hemorrhagic stroke were 0.38% per year on warfarin versus 0.12% on dabigatran 110 mg (P<0.001) and 0.10% on dabigatran 150 mg (P<0.001). Mortality rates were 4.13% per year on warfarin versus 3.74% on dabigatran 110 mg (P=0.13) and 3.64% on dabigatran 150 mg (P=0.05).

There was significantly more dyspepsia

•

see RE-LY, page 9

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Implementing the Recommendations of the Consensus Development Conference:

The Road to Compliance Denis Brown RPh, FASCP Director of Pharmacy—Memorial Campus UMass Memorial Medical Center Worcester, Massachusetts

Introduction New standards for the preparation of IV drugs presented at recent meetings— including the Consensus Development Conference and the American Society of Health-System Pharmacists—constitute a paradigm shift from “traditional” inpatient practice because they place a greater emphasis on safety concerns.1,2 Before United States Pharmacopeia (USP) Chapter <797> was published in 2004, there were generally accepted practice standards that were assumed to produce safe and sterile compounded products; however, there was clearly much room for improvement. In the years since Chapter <797> was published, the challenge for hospital pharmacists continues to center around balancing needs and resources with the newly established standards. One of the Joint Commission’s medication management standards states: “Medications are dispensed in the most ready-to-administer forms commercially available and, if feasible, in unit doses that have been repackaged by the pharmacy or licensed repackager.”3 This standard gives some leverage to hospital pharmacy departments seeking to move toward safer commercially available products and away from pharmacy-compounded. So what steps does a hospital pharmacy need to take to meet the standards, improve compliance, and produce/deliver safer compounded IV medications?

source hierarchy was developed based on the Consensus Development Conference recommendations—as well as guidelines outlined in USP Chapter <797> and by the Joint Commission—and was designed to provide a framework for pharmacists to use when a compounded product was required. Table 1 outlines the source hierarchy implemented and currently in use at UMMMC. This source hierarchy effectively addressed all nonfacility-related (and thus low-cost) changes the pharmacy needed in order to make the move toward compliance; therefore, they could be implemented immediately. Of course, larger capital expenditures (such as the installation or renovation of a clean room) will require additional planning and resources.

Based on the source hierarchy, several changes were made to the processes, as noted in Table 2. In essence, the Pharmacy Department at UMMMC sought to reduce its level of compounding risk by exploring its options in the areas of alternative The Changes products or product configurations. A key At UMMMC, the first step in the action change, for example, involved maximizplan was to establish a new “source hier- ing automated dispensing machine (ADM) archy” for compounded IV solutions within storage of premixed and point-of-care– the center’s Pharmacy Department. This activated IV medications. The benefit of this change was a decreased turnaround time for profiled orders compared with pharmacy-compounded, patient-specifTable 1. Source Hierarchy for Compounded Sterile IV Preparations ic doses. Discontinued doses immediateat UMass Memorial Medical Center ly made unavailable when the order was 1. Maximize frozen premixed products profiled added an additional safety benefit. Ready-to-use doses available on2. Use verified outsourced compounder products (implementation of site improved patient care because delays, verification process, including site visits) that offer the following benefits: omitted doses, and extra doses were no a. extended dating longer an issue. b. high-risk compounding Although this latter change had many c. labeling flexibility to improve safety (ie, “tallman” lettering) benefits, it did result in some new challenges, including the management of 3. On point-of-care–activated orders, ensure: ADM storage of limited stability proda. availability of short-stability medications ucts and shrinkage due to lack of secub. infrequent usage rity in a matrix refrigerated environment. c. improved accessibility and security for vials stored in ADMs The stability of thawed frozen products d. decreased waste requires pharmacists to pay closer attention to expiration dates and par levels for 4. For on-site, clean-room–compounded solutions, ensure: a 14-day stability of a premixed product a. stability (compared with the 12-month expirab. batching tion of a dry vial). Many pharmacies have c. USP Chapter <797> compliance instituted monthly audits of their storage areas to ensure that expired medications 5. For solutions available at countertop, ensure: are removed and that accurate inventory a. immediate use controls are maintained. Also, pharmaADM, automated dispensing machine; IV, intravenous; USP, United States Pharmacopeia cies should implement regular checks of

while functioning under budgetary constraints within this environment, is nothing new, but the most recent recommendations have created a difficult challenge for hospital pharmacies. At UMass Memorial Medical Center (UMMMC)—an 800+ bed academic medical center—the pharmacy team took a multidisciplinary approach to addressing the current processes for changing product selection, medication storage, and dispensing methods. Collaboration and planning were keys to the success of each change, which affected not just pharmacy, but also medical/surgical practice and nursing. Education became a much larger component of the implementation process than first thought.

Hospital pharmacies that prepare compounded sterile IV preparations likely fall significantly short of the practice standards needed for compliance with USP Chapter <797> (ie, staff and facility requirements). As a first step, pharmacies must assess the risk level of the compounding services being performed onsite—most perform low- and medium-risk level compounding—and where their procedures for these preparations fall with regard to Chapter <797>.

After the level of risk has been

The UMass Memorial Medical Center Experience The hospital pharmacy environment is constantly changing. The introduction of new therapies, product shortages, and changes within the medical center are just some of the variables health-system pharmacists must face.

A balancing act between maintaining regulatory and accreditation compliance,

Source: UMass Memorial

6

PHARMACY PRACTICE NEWS • OCTOBER 2009

determined, the next step is a “gap analysis,” which essentially compares a hospital’s current compounding approaches and operational facilities to those recommended in USP Chapter <797> to identify differences or “gaps.”4 The gaps must then be further analyzed to determine priorities with regard to risk and cost. This information, in turn, is used to develop an “action plan” that identifies options for immediately improving compounding practices and reducing vulnerability to microbial contamination and the release of incorrectly compounded preparations.

It should be noted that a completed gap analysis not only sets the objectives for the transition of the hospital pharmacy, it also can be used to demonstrate to accreditation organizations, boards of pharmacy, and other regulatory authorities that the hospital pharmacy is aware of its shortcomings and that action is being taken to improve compliance.

Supported by

Table 2. Summary of Changes Made to Fulfillment Process for Compounded Sterile IV Preparations at UMass Memorial Medical Center refrigeration temperature controls (daily) and power sources to maintain acceptable environmental conditions.

In addition, reminding nursing of the importance of vending of each dose from the ADM to reduce shrinkage is an ongoing process based on the auditing of charges. Once access to the refrigerator is obtained, there is no method to ensure that only the vended item is removed. In an effort to increase efficiency, nurses often may need to remove several products simultaneously, yet vend only one product; as a result, charges and perpetual inventory will be incorrect. To avoid problems, many pharmacies have limited access to storage areas to select personnel and have implemented policies requiring that ready-to-use products are assembled only as needed.

Finally, in some areas point-of-care– activated IV medications were substituted for the premix products. The greater accountability using dry vials in controlled ADM pockets provided longer dating and less shrinkage was balanced against the safety benefits of the premixed products.

As noted during the Consensus Development Conference, all aspects of compounding sterile preparations must be considered as hospital pharmacies attempt to improve USP Chapter <797> compliance. This includes personnel, equipment, and facility options in the main pharmacy, satellite pharmacies, clinics, operating rooms, and nursing workstations.

Training and Implementation At UMMMC, the most significant aspect of the “safety-focused” makeover involved staff education. Simple changes such as switching from a pharmacycompounded product to an outsourced product required basic notification to the pharmacy staff; however, many of these changes also resulted in revisions to the labeling or appearance of the vials. Thus, the end users—the medical/surgical and nursing staff—also needed to be informed.

In general, repeated training sessions were required to reach compliance goals.

One surprising issue was the reaction of the pharmacy staff. The pharmacy had been providing extensive sterile compounding, and staff were reluctant to give up certain compounding in favor of a

New Process

Impact on Pharmacy Workload

Product

Original Process

TPN standard premix

Pharmacy compounded Manufacturer ready-touse

Increased safety, improved stability, improved shelf life, ADM stored

Decreased

Frozen antibiotics

Manufacturer ready-to- Manufacturer ready-touse (patient-specific) use (ADM stored)

Improved turnaround time, decreased omitted and late doses

Decreased

Standardized concentrations

Various concentrations custom compounded

Standardized concentrations were established

Combination of manufacturer/outsourced ready-to-use and batched pharmacy prepared

Decreased

Short-stabilty antibiotics

Pharmacy compounded, limited prep and storage time

Point-of-care activated, vials stored in ADM

Decreased turnaround time

Decreased

High-risk compounds

Pharmacy compounded Outsourced ready-to-use and outsourced readyto-use

Conduct regular site visits and evaluate USP Chapter <797> compliance

Decreased

Syringes for anesthesia

Pharmacy compounded Outsourced ready-to-use or nonpharmacy compounded

Improved safety

Decreased

NICU electrolyte cocktails

Nonpharmacy compounded

Improved safety

Increased

Pharmacy compounded

Comments

ADM, automated dispensing machine; IV, intravenous; NICU, neonatal intensive care unit; TPN, total parenteral nutrition; USP, United States Pharmacopeia Source: UMass Memorial

tighter focused catalog of products sup- an increased volume from a new ambuplemented with alternatives. The chang- latory infusion service and the increase es needed to be justified in terms of effi- in tasks associated with USP Chapter ciencies (ie, decreased workload) and <797> compliance. The increased attenimproved quality. In general, UMMMC’s tion on all sterile products resulted in focus on positive communication empha- a decrease in waste expense. Nursing sizing the improved quality and patient- was very appreciative of the increased care outcomes that resulted from USP accessibility of IV medications. Finally, Chapter <797> requirements, helped “tallman” lettering and other distinctive make implementation of procedural labeling changes have been used to help improve safety with look-alike/soundchanges relatively seamless. alike medications.

In general, USP Chapter <797> comThe Impact pliance helped the pharmacy increase The changes made by the UMMMC safety and improve efficiency and Pharmacy Department were truly “win– documentation. win.” Safety improvements included improved integrity of each sterSummary ile product, improved labeling, tighter The effort to improve compliance with drug security, and better accessibility of first doses. Pharmacy compounding USP Chapter <797> does not end with was focused on select products based implementing initial changes. Monitoron the source hierarchy. The decrease ing the process on an ongoing basis is in the variety of products compounded extremely important. As product availprovided the ability and space to handle ability changes as a result of shortages

and contract modifications, there may be a need to change the process. Using a source hierarchy as a guide, for example, a manufactured product that is unavailable may have to be substituted for an outsourced, point-of-care–activated, or pharmacy-compounded product.

References 1.

Sanborn MD, Moody ML, Harder KA, et al. Second Consensus Development Conference on the safety of intravenous drug delivery systems—2008. Am J Health Syst Pharm. 2009;66(2):185-192.

2.

American Society of Health-System Pharmacists— Best Practices for Intravenous Medication-Use Safety. The IV Safety Summit. http://www.ashp. org/iv-summit. Accessed August 6, 2009.

3.

The Joint Commission. Long-Term Care Accreditation Program. 2009 Chapter: Medication Management. www.jointcommission.org/. Accessed August 6, 2009.

4.

American Society of Health-System Pharmacists—Discussion Guide for Compounding Sterile Preparations. www.ashp.org/s_ashp/docs/files/ HACC_797guide.pdf. Accessed August 6, 2009.

PHARMACY PRACTICE NEWS • OCTOBER 2009

7

with distinct labeling from Baxter.

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To learn more, contact your Baxter representative or call 1-800-4-BAXTER (1-800-422-9837).

Baxter, Committed to a Safer Healthcare Environment, and the distinctive product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111085 03/09

Clinical 9

Pharmacy Practice News • October 2009

Cardiology In acute coronary syndrome …

Investigational Agent Trumps Clopidogrel Barcelona, Spain—The investigational drug ticagrelor significantly reduced the rate of cardiovascular death compared with clopidogrel in a large, multicenter, Phase III, head-to-head study presented at the 2009 Congress of the European Society of Cardiology.

Results of the PLATO (PLATelet inhibition and patient Outcomes) trial showed that ticagrelor (AstraZeneca) produced a significant 16% relative risk reduction and a 1.9% absolute reduction in the composite end point of death from vascular causes, myocardial infarction (MI) or stroke compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis).

Ticagrelor exerted the protective effect without an increase in bleeding, lead author Lars Wallentin, MD, PhD, professor of cardiology at Uppsala Clinical Research Center, in Sweden, told Congress attendees at a hotline session. The trial was published online in The New England Journal of Medicine (2009;DOI:10.1056/NEJMoa0904327).

Ticagrelor, which AstraZeneca plans to market under the trade name Brilinta, is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12, and has a more rapid onset and more pronounced platelet-inhibiting ability than clopidogrel.

“Current clinical practice guidelines for patients with acute coronary syndrome [ACS] recommend dual antiplatelet treatment with aspirin and clopidogrel,” Dr. Wallentin said. “However, the efficacy of clopidogrel is hampered by slow and variable transformation of the prodrug to the active metabolite, modest and variable platelet inhibition, increased risk of bleeding, and increased risk of stent thrombosis and myocardial infarction in poor responders.”

Ticagrelor has potential advantages over clopidogrel, he said. “It is a directacting compound, it is not a prodrug; it does not require metabolic activation; it has a rapid onset of the inhibitor effect; and it provides greater inhibition of plate-

RE-LY continued from page 4

with dabigatran—11.8% with the low dose and 11.3% with the high dose, compared with 5.8% with warfarin (P<0.001).

Discussant A. John Camm, MD, professor of medicine at St. George’s University of London, said RE-LY raises many questions. “Which of the two doses should we choose? How do we tailor therapy for our patients? Should we change patients who are satisfacto-

Patients randomized to clopidogrel (n=9,291) received the standard 300-mg loading dose only if they were clopidogrel-naïve, and then 75 mg clopidogrel once daily as a maintenance dose thereafter. Patients going on to a PCI procedure were allowed an additional 300 mg of clopidogrel at the discretion of the individual physician. Patients randomized to ticagrelor (n=9,333) received a 180-mg loading dose, then 90 mg twice daily as maintenance thereafter. Patients in the ticagrelor arm who were going on to PCI received an additional 90-mg dose before the procedure.

The study’s primary end point was a composite of cardiovascular death/MI/ stroke, and its primary safety end point was total major bleeding.

The patient population (median age, 62 years) represented a moderate- to highrisk ACS population. At 12 months, the primary end point had occurred in 9.8% of patients receiving ticagrelor compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77-0.92; P<0.001).

Rates of predefined secondary end points were also significantly reduced for ticagrelor versus clopidogrel at

12 months. These included all-cause mortality/MI/stroke (10.2% vs. 12.3%; P<0.001), cardiovascular death/MI/ stroke/severe recurrent ischemia/ recurrent ischemia/transient ischemic attack/other arterial thrombotic event (14.6% vs. 16.7%; P<0.001), MI alone (5.8% vs. 6.9%; P=0.005), cardiovascular death (4.0% vs. 5.1%; P=0.001) and total mortality (4.5% vs. 5.9%; P<0.001).

“The reduction in total mortality was the largest reduction seen, a 22% relative reduction of total mortality and a 1.4% absolute reduction, strongly significant,” Dr. Wallentin said. “There was a continuous benefit of ticagrelor over time.

During the entire treatment period, you have a lower event rate in patients on ticagrelor versus clopidogrel.”

There was no difference between the agents with regard to total major bleeding (11.2% for ticagrelor vs. 11.6% for clopidogrel; P=0.434). However, non– CABG-related major bleeding occurred significantly more frequently with ticagrelor than clopidogrel (4.5% vs.

3.8%; P=0.026).

Episodes of dyspnea were more common with ticagrelor than clopidogrel (14.2% vs. 9.2%), and this side effect led to discontinuation of treatment in 1.0% and 0.3% of patients, respectively. Ventricular pauses, detected by Holter monitoring, were more frequent in the ticagrelor group than in the clopidogrel group, particularly in the first week of treatment (5.8% vs. 3.6%; P=0.01). These became less frequent at 30 days, occurring in 2.1% of the ticagrelor group and 1.7% of the clopidogrel group (P= 0.52).

In his discussion of the PLATO trial, Steen Dalby Kristensen, MD, professor of medicine at Aarhus University, in Aarhus, Denmark, pointed out that patients with active bleeding, a bleeding history or severe anemia were excluded from the study. As a result, the bleeding profile of ticagrelor should be tested in “realworld” ACS patients, he said.

Dr. Kristensen also noted that it was not surprising that ticagrelor was not

associated with an increased incidence of CABG-related bleeding, because “one of the major advantages of reversible inhibition of P2Y12 is indeed the possibility of reducing bleeding during surgery.”

He also raised the possibility that ticagrelor’s 12-hour half-life, which necessitates twice-daily dosing, as well as its reversible receptor binding, might be a problem in patients who are not fully compliant. “Compliance in this trial was approximately 83% in each group. Implementation of ticagrelor might be troublesome in patients who are unable to fully adhere to the prescribed drug therapy, because insufficient platelet inhibition increases the risk of stent thrombosis and other ischemic events.”

Nevertheless, Dr. Kristensen concluded that ticagrelor is a promising drug. “In ACS, it seems to have better efficacy, so even if there might be a few more bleedings, these bleedings might be easier to treat because of the reversibility of the drug and also because it is easier for us to manage in patients undergoing operations or other procedures.”

rily managed on warfarin to dabigatran?

Do the elderly fare as well with dabigatran as does the trial group as a whole?

Does it matter that there is no antidote to dabigatran? Will you or your patients feel comfortable when you are unable to monitor the degree of anticoagulation?” [Unlike warfarin, dabigatran does not require dose adjustments or anticoagulation monitoring.]

William Dager, PharmD, BCPS, pharmacist specialist, UC Davis Medical Center, Sacramento, said the RE-LY data “are

encouraging.” However, he stressed that warfarin still retains some benefits over dabigatran. Warfarin’s rapid decline of activity, for example, “can be an advantage in patients needing oral bridge therapy.”

Another advantage of warfarin is the frequent contact with caregivers that occurs as a result of the drug’s monitoring requirements. During those visits, “patients get continuous reinforcement to take their medications as prescribed,” Dr. Dager said. “That’s always valuable, especially with anticoagulants.”

He added that in RE-LY, dabigatran was discontinued more frequently than warfarin, “suggesting that not all patients will be candidates for this therapy.” Other key issues, such as drug interactions and the need for dosage adjustments in patients with renal insufficiency, “still need further clarification in general use to ensure that the risk of adverse events associated with [dabigatran] are minimized.”

let aggregation than clopidogrel. It is reversibly bound to the platelets and the degree of inhibition reflects plasma concentration. It has a faster onset of effect than clopidogrel and there is a functional recovery of all circulating platelets after cessation of treatment.”

PLATO included 18,624 patients enrolled from 43 countries, who were admitted to hospital either with ST-elevation ACS and slated to have primary percutaneous coronary intervention (PCI; 38%), or with non–ST-elevation ACS and due to have invasive or medical treatment (62%). Both clopidogrel-treated and clopidogrel-naïve patients were included in the study. Before randomization, 94% of patients were treated with aspirin and 46% with clopidogrel.

Loading Dose Details

Pharmacist’s Perspective Commenting on the PLATO trial and ticagrelor for Pharmacy Practice News, Sarah A. Spinler, PharmD, professor of clinical pharmacy at the Philadelphia College of Pharmacy, University of the Sciences, voiced a few cautionary notes. She pointed out that ticagrelor is metabolized by CYP3A4, and “patients receiving strong inhibitors, substrates or agents with a narrow therapeutic range, like cyclosporine, were excluded from the trial.” She added that the mechanism of dyspnea as an adverse event has not yet been fully described, although few patients discontinued ticagrelor for that reason. Still, it is a side effect that will need to be explained to patients.

Finally, “ticagrelor also causes ventricular pauses, which may be of concern in some patients receiving concomitant heart rate–lowering drugs.”

—Fran Lowry

—Fran Lowry

10 Pharmacy Heritage

Pharmacy Practice News • October 2009

They Didn’t Come Home Honoring pharmacy’s fallen on Veterans Day

A

Stories of Sacrifice David Edward Nolte was a 1927 graduate of the University of Tennessee, Memphis; he owned a pharmacy in Yazoo City, Miss. He enlisted in the Navy in May 1942, despite the fact that at 37 years of age, he was old enough to be exempted from the draft. He reported for duty on the USS Reid in July 1943, as a Chief Pharmacist Mate. The oldest man on the ship, he was recently remembered by his former executive officer as a father figure, well respected and liked. The USS Reid (DD369), a modern destroyer, was in Pearl Harbor for maintenance on Dec. 7, 1941, and emerged from the chaos unscathed.

The ship had a distinguished combat record and, in December 1944, was part of the Seventh Fleet at the Battle of Leyte Gulf in the Philippines. While guarding amphibious craft on Dec. 11, the USS Reid was attacked by seven enemy aircraft from Japan, three of which crashed into the destroyer, sinking her within minutes.

Mortally wounded, Chief Pharmacist Mate Nolte did not come home.

Edward Vassar Stephenson was a 1937 graduate of the North Carolina College of Pharmacy and a pharmacist in

Sombongse Salyabongse, a 1942 graduate of the Philadelphia College of Pharmacy, died in the custody of Thai police while working to support resistance fighters during World War II.

Second Lt. Ronald Helder (second from left, standing) was a pharmacist and crew member of the B-24 bomber “Ole Kickapoo.” He and seven other crew members died when their plane was shot down during a low-level bombing raid against the Romanian oil fields at Ploesti.

More than 11,000 pharmacists and student pharmacists were among the 16 million men and women who served in the armed forces of the United States during World War II.

Seeking the Full Measure of Sacrifice

T

he stories of the approximately 150 pharmacists who are known to have died in battle during World War II are compelling. But they don’t give a complete account of the profession’s sacrifice during the conflict, according to Dennis B. Worthen, PhD, Lloyd Scholar at the Lloyd Library and Museum in Cincinnati.

To remedy that information gap, Dr. Worthen is embarking on a research project that will document more fully the extent of pharmacy’s fallen during WWII. Because of the young age of these men when they died, he said, it’s not surprising that a more complete The American Cemetery, Omaha Beach, account is not yet available.

“They were called to service as Normandy, France. young men, and very few of them had children before they died,” Dr. Worthen said. “Over the years, their parents and siblings have passed on, and memories of those fallen kin have slowly disappeared. It’s almost as if these young men had never been alive; as if their lives had no significance. That’s something I hope to change with this research project.”

Although the project is still in development, Dr. Worthen has started contacting military and veterans organizations in an effort to identify the war experiences of the fallen. Colleges of pharmacy in operation during the war, state pharmacy associations and state libraries and archives are among the groups that will be contacted to identify names of additional pharmacists killed in action, he said.

Dr. Worthen estimated that the project will take about two years to complete.

It will be finished, he said, when no additional pharmacists/students are identified as killed in action, and no new information about those already identified as fallen can be obtained.

If you have any information about a pharmacist or student pharmacist who died while on active duty in World War II, Dr. Worthen asks to be contacted at dbworthen@lloyd.library.org.

—David Bronstein

CREDIT: Denni Dennis B B. Wo Worthen, then PhD PhD.

Navy man who was old enough to stay home, but instead enlisted, only to die in a battle at sea; a Marine who made it through two invasions in the Pacific before being killed in a fierce airfield battle on Iwo Jima; an Army Air Forces pilot who went down with his B-24, but not before hitting all of his targets during a bombing run over Eastern Europe.

These are just a few examples of the approximately 150 pharmacists who died as a result of enemy action during World War II. On Veterans Day, Nov. 11, we honor these brave men and reflect on the profession’s military contributions.

More than 11,000 pharmacists and student pharmacists were among the 16 million men and women who served in the armed forces of the United States during World War II. At that time, the military did not recognize pharmacy as a profession; pharmacists were not commissioned to serve in their professional roles, although many were commissioned to serve in other capacities.

It was a period when many pharmacists put themselves in harm’s way as corpsmen, medics, air crews, infantry and sailors, and many of them never came home. A new project documenting their lives and deaths is now in progress (sidebar).

Madison, N.C., when he enlisted in the Marine Corps in July 1942. After training, he was commissioned and sent to the Pacific, where he took part in the invasion of Bougainville in November 1943 and the invasion of Guam in 1944.

Stephenson was promoted to captain and a company commander in time for the Iwo Jima invasion, which took place Feb. 19 through March 26, 1945.

In late February 1945, Stephenson rallied his company against a Japanese tank attack. During the advance on Motoyama Airfield No. 2, he was killed by enemy fire.

Capt. Stephenson did not come home.

Ronald Helder was a 1940 graduate of the South Dakota State College Division of Pharmacy, as it was then known. After enlistment, Helder went through pilot training in the Army Air Forces, was commissioned as a second lieutenant and assigned to B-24 bombers. He joined the crew of Lloyd “Pete” Hughes as a co-pilot. Their B-24 (Ole Kickapoo) arrived in Benghazi, Libya on July 1, 1943, and took part in several bombing raids on Italy. On Aug. 1, Ole Kickapoo joined 176 other B-24s in Operation Tidal Wave, the low-level bombing raid against the Romanian oil fields at Ploesti. Fifty-four planes and 532 crew members were lost, including eight crew members of Ole Kickapoo.

An eyewitness account related that the

Pharmacy Heritage 11

Pharmacy Practice News • October 2009

Dennis B. Worthen, PhD, the author of “Pharmacy Heritage,” is the Lloyd Scholar at the Lloyd Library and Museum in Cincinnati. He can be reached at dbworthen@lloydlibrary.org

part of their training at Fort Dix, N.J. The 15th General Hospital was eventually located in Liege, Belgium, which became a major target for German “V” rockets in late 1944. The “V” rockets could not be accurately aimed as the residents of London well knew, and the same was true in the supply dumps and service areas surrounding Liege. On Nov. 24, a rocket hit the 15th General Hospital, killing a number of personnel; Malmo and Petrick were likely killed in that attack.

Student pharmacists Malmo and

aircraft had been hit and was spewing gasoline but the pilot refused to break formaDennis B. Worthen, PhD tion and dropped his bombs perfectly on target. Hughes was subsequently awarded the Congressional Medal of Honor; 2nd Lt. Helder and the other crew members received the Distinguished Service Cross.

Second Lt. Helder did not come home.

The Long Way Home

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Coming home had a different meaning for Sombongse Salyabongse, or Sal. Sal was from Thailand, a 1942 graduate of the Philadelphia College of Pharmacy. Thailand was under the control of the Japanese, but a Free Thai group had been formed in the United States with the aid of the Office of Strategic Services (OSS). Sal was recruited and trained by the OSS to return to Thailand to provide support and liaison with the underground. In the spring of 1944, Sal and his partner left their base in China to cross northern French Indochina and enter Thailand. Stories vary, but the pair was arrested by Thai police and was being held for Japanese authorities when they were killed in June 1944.

Although Sal did get back to Thailand, like the others, he did not come home.

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information.

WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose.

For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).

An Early, Tragic End To a Profession

CREDIT: Dennis B. Worthen, PhD.

As for student pharmacists who were killed in action, information on their stories has been more difficult to find.

Due to their youth, they had little pharmacy experience and most had a short military career before their death. Marion Petrick and Lee Malmo were both students at North Dakota State University. They may have been inducted at the same time if their serial numbers are any indication; they were only 10 digits apart. Both were assigned to the 15th General Hospital and received

The “Iron Mike” memorial in Normandy, France, honors the U.S. 82nd Airborne Division’s capture of the La Fière bridge, a key objective during the allied invasion.

Petrick did not come home.

The stories of these and other young men, killed in their prime, far from home are becoming harder to find.

Unlike others of the Greatest Generation, they did not come home to record their memories. Additionally, few had surviving parents, siblings or children to tell their stories for them.

Their stories are with the Marines at Iwo Jima and Guadalcanal, with the Army at the Battle of the Bulge and Normandy, with the Air Force in the skies over China and Romania, and at sea at Leyte and Anzio. The

1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions.

1.1 Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI).

This includes, but is not limited to, the humoral immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts.

3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion.

4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia.

Privigen is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]).

5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]).

5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and benefits of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered.

5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS

current research project is an attempt to document their lives, pharmacy and military, so that we will not forget them.

The charge, eloquently expressed by Maria B. Orlowski in her commencement address in 2009 at Albion College, in Albion, Mich., is to “reclaim the dead from the death of nonremembrance.”

Suggested Reading Worthen DB. Pharmacy in World War II. Binghamton, NY: Pharmaceutical Products Press; 2004.

Worthen DB. Pharmacists in wartime: a brief overview with words and images from the memories project. J Am Pharm Assoc. 2001;41:479-489.

within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data.

Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Privigen infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.

Monitor patients for pulmonary adverse reactions (see Patient Counseling Information [17]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum.

TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded fluid volumes or where fluid volume may be of concern (see Dosage and Administration [2.2]).

5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]).

5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter.

Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum.

5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills.

The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects.

Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia.

6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice.

Treatment of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female.

The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A

12 Clinical

Pharmacy Practice News • October 2009

Infection Control

STEWARDSHIP continued from page 1

The recommendations paralleled those of the daptomycin package insert, except for increasing the dosage for VRE by one-third to 8 mg/kg. The main reasons for initiating the protocol, according to the investigators, were the increasing use of the antibiotic at the large, private, tertiary-care teaching hospital and the rising minimum inhibitory concentrations (MICs) for VRE seen at the hospital and elsewhere.

“For two to three years, we’ve seen

more use of daptomycin as our MICs for vancomycin have crept up,” said Kevin Garey, PharmD, associate professor and chair of the Department of Clinical Sciences and Administration at the University of Houston College of Pharmacy, adding that at St. Luke’s “a vancomycin MIC of 1 against MRSA is quite common.”

In a medication use evaluation (MUE) conducted before the protocol, Betsy Hirsch, PharmD, infectious diseases pharmacy fellow at St. Luke’s and the University of Houston School of Pharmacy, prospectively reviewed charts of all patients who received daptomycin

total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males.

Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered.

Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period.

Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality.

Table 2: Adverse Events Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.

Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects).

Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other).

Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.

During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).

Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male.

Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine.

Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality.

Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased

Subjects (%) [n=57] 37 (64.9) 21 (36.8) 6 (10.5) 6 (10.5) 6 (10.5)

Infusions (%) [n=114] 41 (36.0) 22 (19.3) 6 (5.3) 6 (5.3) 6 (5.3)

6 (10.5)

6 (5.3)

5 (8.8)

5 (4.4)

4 (7.0) 3 (5.3)

4 (3.5) 3 (2.6)

during October 2008. Dr. Hirsch and her colleagues collected data on indications, dosages, frequency, microbiology, comorbidities, laboratory values and patient outcomes. After the protocol was introduced in February, the team followed up with a second prospective MUE, gathering information in the same categories for April.

In comparing the two study periods, the investigators found that physicians had ordered 32 courses of daptomycin in the earlier month and 36 in the later one.

The proportion of empiric use decreased to 50% in April from 72% in the pre-

Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen.

One subject withdrew from the study due to gingival bleeding, which was not related to Privigen.

Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention.

Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis.

In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29.

Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period.

6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance.

Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products.

General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility.

The following adverse reactions have been identified and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information [17]).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen.

It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated.

8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3.

Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15.

8.5 Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable.

Manufactured by: CSL Behring AG Bern, Switzerland

* Two consecutive daily infusions.

Of the 183 temporally associated AEs reported for the 57 subjects with chronic ITP, the investigators judged 150 to be related to the infusion of Privigen (including the one serious AE described below). Of the 149 non-serious AEs related to the infusion of Privigen, 103 were mild, 37 were moderate, and 9 were severe. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (65% of subjects) and pyrexia/hyperthermia (35% of subjects).

US License No. 1766 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Based on June 2009 revision.

protocol period. Additionally, they found decreases in both mean duration of therapy (8±9.2 vs. 6.4±4.5 days) and empiric use duration (6±3.9 vs. 4.7±2.9 days).

Moreover, patients were more likely to receive optimal doses in the post-protocol period (odds ratio, 2.175; 95% confidence interval, 0.74-6.13; P=0.147).

A CASE of Collaboration The St. Luke’s stewardship program is directed by the hospital’s Center for Antimicrobial Stewardship and Epidemiology (CASE), a collaborative body comprising the pharmacy department, infection control, ID physicians and other interested physician groups at the hospital. The pharmacy department employs two full-time infectious disease pharmacists, Hannah Palmer, PharmD, and Jaye Weston, MS, who coordinate the program. In all, about 30 people attend meetings monthly or every six weeks to discuss policy issues and plan educational strategies for antimicrobial initiatives. Approximately 10 pharmacists, including ID specialists and fellows, the pharmacy director and university clinical staff, sit in regularly.

‘[S]tewardship programs are not about cost containment or [being the] antibiotic police anymore. They are about doing the best job with the antibiotics we have.’

—Kevin Garey, PharmD Dr. Garey said daptomycin prescribing had greatly improved as a result of the educational program that accompanied the restrictive protocol launch, and pharmacist monitoring had helped to keep the effort on track. Now, he said, ID pharmacists or ID pharmacy fellows evaluate all daptomycin orders on a daily basis.

The surveillance effort, he said, had resulted in discovering “a lot of serious errors,” including “a couple of cases where daptomycin was being used inappropriately. They’ve really done an amazing job of taking care of the problem.”

Only a Partial Solution Craig Martin, PharmD, BCPS, clinical pharmacy specialist in infectious diseases, University of Kentucky, in Lexington, noted that “the principles of antimicrobial stewardship should be at the center of any effort to reduce antimicrobial resistance. Using antimicrobials wisely can improve patient outcomes, minimize adverse effects and reduce resistance in key pathogens.”

Clinical 13

Pharmacy Practice News â&#x20AC;˘ October 2009

Infection Control Dr. Martin added, however, that â&#x20AC;&#x153;antimicrobial stewardship can only be effective if adequate infection prevention and control is also observed. If patients are acquiring multidrug-resistant organisms from the health care environment, limiting antibiotic use may have little effect. Used in concert, antimicrobial stewardship and infection prevention and control can be very successful in limiting resistance.â&#x20AC;?

Richard H. Drew, PharmD, MS, BCPS, professor at Campbell University College of Pharmacy and Health Sciences and associate professor of medicine (Infectious Diseases) at Duke University School of Medicine, Durham, N.C., noted that â&#x20AC;&#x153;the data regarding rising vancomycin MICs and poor outcomes for invasive MRSA infections are driving us to alternative agents like daptomycin. That may be appropriate, but if you indiscriminately use daptomycin or linezolid [Zyvox, Pfizer], then youâ&#x20AC;&#x2122;re going to have a different problem, an economic problem.â&#x20AC;?

As for the protocolâ&#x20AC;&#x2122;s higher daptomycin

dosage for VRE, Dr. Drew said the hospitalâ&#x20AC;&#x2122;s response was apparently based on the premise that the needed drug exposure should be relative to the susceptibility of the organism. â&#x20AC;&#x153;They were seeing that the MICs were higher for VRE than for MRSA. Since that particular drug exhibits concentration-dependent killing, they intensified the dose.â&#x20AC;?

Dr. Drew added, â&#x20AC;&#x153;Is that what we do here at Duke? Do we automatically increase the dose for enterococci? Not always, and we donâ&#x20AC;&#x2122;t do it as a standard policy. But I can understand what motivated them to do that.â&#x20AC;?

Dr. Garey said that one effect of the restrictive protocol has actually been to increase the total use of daptomycin at St. Lukeâ&#x20AC;&#x2122;s, â&#x20AC;&#x153;increasing the doses and utilization of the agent, but more appropriately.

It really highlights that stewardship programs are not about cost containment or [being the] antibiotic police anymore.

They are about doing the best job with the antibiotics we have.â&#x20AC;? â&#x20AC;&#x201D;Bruce Buckley

In Brief

Pharmacists Excel at Managing Antibiotic Rx for Cystic Fibrosis Anaheim, Calif.â&#x20AC;&#x201D;Pharmacists may be the best members of the hospital care team to manage the antibiotic drug therapy of patients with cystic fibrosis (CF), a new study suggests.

The research showed that 27% more patients with CF achieved key pharmacokinetic/pharmacodynamic (PK/PD) targets when managed by pharmacists versus non-pharmacist practitioners, according to lead author Jeffrey J. Cies, PharmD, BCPS, pharmacy clinical coordinator, St. Christopherâ&#x20AC;&#x2122;s Hospital for Children, in Philadelphia.

Dr. Cies said the idea for adding a clinical pharmacist to the CF care team â&#x20AC;&#x153;makes senseâ&#x20AC;? in light of how difficult it can be to manage infective pulmonary CF exacerbations due to Pseudomonas aeruginosa. â&#x20AC;&#x153;It can really be a challenge to achieve PK/PD targets in these patients, who typically get aminoglycosides,â&#x20AC;? he said. â&#x20AC;&#x153;If you fail, it can lead to poor outcomes and the development of resistance.â&#x20AC;?

The retrospective cohort study, presented at the annual meeting of the American College of Clinical Pharmacy, began in January 2007. Included in the analysis were patients with CF who received an aminoglycoside and had at least two serum concentrations

that allowed determination of PK/PD parameters. Baseline demographic data were similar between the groups.

To date, 29 patients given 52 courses of aminoglycoside therapy have been included in the pharmacist (P) group versus 22 patients given 42 courses of aminoglycosides in the non-pharmacist group (NP). According to the investigators, 98% of patients in the P group reached aminoglycoside PK/PD targets compared with 71% in the NP group (P<0.001). â&#x20AC;&#x153;Thatâ&#x20AC;&#x2122;s nearly a 30% difference, and we think it shows that pharmacists can potentially do a better job than other caregivers when it comes to managing the drug therapy of patients with cystic fibrosis,â&#x20AC;? Dr. Cies said. â&#x20AC;&#x153;We also found that patients in the pharmacist-treated group attained aminoglycoside PK/PD targets earlier, which could improve care and response to therapy and minimize costs related to dosage adjustments and drug wastage.â&#x20AC;?

Specifically, the P group was at treatment goal in a mean of 1.98 days compared with 4.77 days in the NP group (P<0.0001). Data collection and analysis are still ongoing, the investigators noted. â&#x20AC;&#x201D;David Bronstein

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Hem/Onc Pharmacy

Pharmacy Practice News • October 2009

In Focus

TKIs Beat Chemo for NSCLC Patients With EGFR Mutations M ounting evidence indicates that tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva, Genentech) and gefitinib (Iressa, AstraZeneca), are a better choice than chemotherapy for patients with advanced, non-small cell lung cancer (NSCLC) who have a mutation in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) pathway. Data suggest that clinicians should obtain tumor tissue and assess it for EGFR mutational status before treating patients. The growing evidence is already beginning to shift routine care of unresectable NSCLC.

A Second Life for Gefitinib?

Perhaps the strongest support for TKIs in lung cancer comes from two gefitinib studies, begging the question of whether the drug may have a second life in the United States. A study conducted in Japan presented at the recent joint meeting of the European Cancer Organisation and Congress of the European Society for Medical Oncology (ECCO-ESMO; abstract LBA9) showed that first-line gefitinib trumps carboplatin and paclitaxel therapy in the treatment of patients with advanced NSCLC who have EGFR mutations. The study randomized 200 of the patients to receive either gefitinib (250 mg/day) or carboplatin (AUC 6) plus paclitaxel (200 mg/m2) in 21-day cycles. Patient characteristics were well balanced in the two arms. An interim analysis, conducted in May 2009 on 198 patients, revealed a significantly longer median progression-free survival (PFS) in patients receiving gefitinib, 10.4 vs. 5.5 months (hazard ratio [HR], 0.357; P<0.001). Because of this, the independent safety committee recommended terminating accumulation of patients.

The study also revealed a significantly higher response rate in patients receiving gefitinib (74.5% vs. 29.0%; P<0.001).

Analysis of preliminary survival data did not reach statistical significance. Grade 4 neutropenia (1% vs. 33%) and grade 3 neuropathy (0% vs. 5%) were more prevalent in patients receiving gefitinib, and grade 3-4 liver dysfunction (25% vs.

1%) was higher in patients receiving the combination therapy (P<0.01).

“Gefitinib should be the standard for first-line therapy for advanced NSCLC with sensitive EGFR mutations,” said lead author Akira Inoue, MD, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohuku University, Sendai, Japan.

Further evidence comes from updated findings from the randomized IPASS (IRESSA Pan-ASia Study) presented at the World Conference on Lung Cancer (abstract B9.7). In the original open-label

study, presented at the 2008 European Society for Medical Oncology Congress, the HR for PFS among the 1,217 nonsmokers (<10 packs lifetime and no smoking in the last two years) was 0.74 (P<0.0001) in favor of gefitinib over carboplatin/paclitaxel. When stratified by EGFR mutational status in a new post-hoc analysis, the HR for PFS favoring gefitinib fell to 0.377 among subjects with the exon 19 deletion and 0.553 among those with the leucine substitution at amino acid 858 (L858R). Thirty-six percent of patients participating in the study had tumor tissue available for evaluation.

“Gefitinib had greater efficacy than carboplatin/paclitaxel in both of the major EGFR mutation subgroups, although there was a slightly greater relative advantage for those with the exon 19 deletion,” said Tony S.K. Mok, MD, a professor in the Department of Clinical Oncology, Chinese University of Hong Kong, in China.

In addition to the significant increase in PFS, gefitinib was also associated with a significantly greater improvement in quality of life compared with chemotherapy. There was also a relative advantage for objective response and rates of symptom improvement, but the difference reached significance only for those with the exon 19 deletion. The most common EGFR mutations are exon 19 deletions and L858R point mutations in exon 21.

Both are implicated in blocking Akt pathway signaling that promotes apoptosis.

trials related to this agent have been designed to focus on patients with EGFR mutations rather than the broader population of NSCLC patients,” said Michael Fisch, MD, medical director of the Clinical Community Oncology Program at M.D. Anderson Cancer Center in Houston. “Just like we have epoetin alfa and darbepoetin, we’ll have gefitinib and erlotinib—drug duos that serve the same role in patient care.”

Philip Bonomi, MD, director of the Division of Hematology-Oncology at Rush University Medical Center, Chicago, agreed. “I believe that reapproval of Iressa should be considered based not only on the IPASS data, but also on the results of the INTEREST study,” he said. Richard Gralla, MD, president of the New York Lung Cancer Alliance, said he thought Iressa could have a second life but was not convinced that the drug was better than others currently available.

A spokesperson from AstraZeneca said the company looked forward to a dialogue with the FDA about the new data, but would not provide further details.

Regulatory Roadblocks

Pooled Evidence

So, can gefitinib overcome FDA restrictions on its use? Initially approved in 2003, the agency altered the status of the drug in 2005 after a large randomized study ISEL (Iressa Survival Evaluation in Lung Cancer) showed that the drug failed to significantly improve survival in patients with chemo-refractory NSCLC compared with placebo (Lancet 2005;366:1527-1537). The drug’s label was changed to indicate that only cancer patients who had already taken the medication and whose physicians believed that it was helping could receive the drug. No newly diagnosed lung cancer patients in the United States were given gefitinib after this time, but the drug remained a therapy in other countries.

In 2008, the INTEREST (IRESSA Nonsmall-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study demonstrated that gefitinib had similar activity to chemotherapy with docetaxel in previously treated patients (Lancet 2008;372:1809-1818). This study also showed an improved response and PFS in EGFR mutation-positive patients.

“I do think that gefitinib will have a second life in the U.S. now that the

In a study presented at the recent World Conference on Lung Cancer (abstract B9.7) of the International Association for the Study of Lung Cancer, researchers conducted a pooled analysis that collated data from all NSCLC studies that have evaluated EGFR mutational status.

According to the senior author of the study, Luis Paz-Ares, MD, Oncology Service, Hospital Universitario Virgen del Rocío, in Sevilla, Spain, the TKIs erlotinib and gefitinib beat chemotherapy for the end point of PFS, whether they were used first- or second-line. Based on these results, Dr. Paz-Ares characterized EGFR TKIs as “an attractive prospect in patients with EGFR-mutant advanced NSCLC.” The pooled analyses were based on studies that included PFS data, mutational status, and treatment with chemotherapy or either erlotinib or gefitinib. The majority of data came from published Phase II and III studies. There were 413 NSCLC patients treated with gefitinib in 13 studies, 341 patients treated with erlotinib in eight studies and 192 patients who were treated with chemotherapy in six studies. To permit a weighted analysis, the percentage of progression-free

Diagram of the epidermal growth factor receptor.

survivors at a fixed time point was evaluated using a formula based on assumptions of PFS distribution.

When the treatment strategies were compared in the first-line setting among patients with EGFR mutations, the pooled median PFS was 13.6 months for erlotinib, 9.7 months for gefitinib and 6.4 months for chemotherapy. The distribution of PFS rates for second-line treatment with TKIs was similar. Again, erlotinib led with the longest median PFS of 13.3 months, gefitinib came second with a median PFS of 8.8 months, and chemotherapy resulted in the shortest median PFS at 4.1 months.

Until recently, according to Dr. PazAres, it has been “difficult to conduct large-scale investigations of possible associations between EGFR mutations and therapeutic outcomes because of the limited availability of tissue samples.”

This, however, is likely to change. The ongoing Phase III EURTAC (European Randomized Trial of Tarceva vs Chemotherapy) study, a randomized comparison of erlotinib and chemotherapy, is among a growing number of studies whose protocol requires biopsy and is looking closely at molecular markers, including EGFR mutations, to determine which patients benefit most.

The ability of TKIs to provide a far more profound effect on cancer growth than traditional cytotoxic agents suggests a paradigm shift away from nonspecific cytotoxic agents to drugs targeted at vulnerable molecular processes. While Dr. Paz-Ares speculated that EGFR-mutant NSCLC “may be considered as a distinct disease within the broader spectrum of NSCLC,” the same may be said for other forms of NSCLC that can be categorized by a molecular or genetic profile.

Recently, there has been surging interest in identifying molecular profiles that can help predict treatment response in a broad variety of cancers, not just NSCLC. For example, several guidelines now recommend that patients with colorectal cancer who are candidates for cetuximab (Erbitux, ImClone) should first undergo tissue sampling to confirm the K-ras

•

see TKIs, page 40

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Pharmacy Practice News • October 2009

In Focus

Higher Dose of Imatinib May Improve CML Outcomes San Francisco—New data from a series of large trials lend support to the idea that intensification of first-line imatinib in patients with chronic myeloid leukemia (CML) may improve outcomes.

Of four studies designed to address this topic, three suggested that either increasing the dose or adding a second agent such as cytarabine (ARA-C) or pegylated interferon (PEG-IFN) improved response rates. Although a fourth study did not associate a higher imatinib dose with a significantly improved response on an intention-totreat (ITT) basis, there was a higher rate of cytogenetic response in those who tolerated the higher dose.

The series of studies, all presented at the recent annual meeting of the American Society of Hematology, address a major clinical issue. Although imatinib has been a highly effective therapy for patients with newly diagnosed CML, major studies such as IRIS (International Randomized study of Interferon and ST1571) indicate that 20% to 30% of patients do not do well on a standard 400-mg imatinib dose and require alternative therapies. Reducing this percentage is an important clinical goal.

“The standard first-line therapy for newly diagnosed CML is 400 mg of imatinib daily, but 50% to 60% [of patients] will not achieve a complete cytogenetic response [CCyR] at 12 months,” said Francois Guilhot, MD, Centre Hospitalier Universitaire de Poitiers, France, lead investigator of two of the studies.

The goal of both of the studies presented by Dr. Guilhot was to evaluate strategies to boost early response in order to improve late outcome.

TOPS Trial Of the two trials, TOPS (Tyrosine Kinase dose Optimization Study) may be the most important as a proof of principle (abstract 447). In this multicenter, Phase III, open-label study, more than 800 patients received either 400 or 800 mg (400 mg twice daily) imatinib, but response rates were evaluated in the context of trough plasma levels regardless of dose. When stratified into quartiles, the major molecular response rates at 12 months were more than 50% greater among patients with the highest trough concentration of imatinib compared with those with the lowest (59% vs. 38%; P=0.0338; Figure).

Although it also was true that patients with the highest trough plasma concentrations also had the greatest frequency of adverse events, Dr. Guilhot indicated that drug exposure does appear to predict response. He suggested that some form of drug monitoring might

be needed to maximize the risk–benefit ratio of imatinib therapy.

European LeukemiaNet Although another trial addressing the same topic produced a negative result, the data may support the same conclusion. Conducted specifically in patients labeled as high risk based on Sokal score, the ongoing European LeukemiaNet study (abstract 185) randomized 217 treatment-naïve patients with Philadelphia chromosome–positive CML (CML Ph+) to 400 or 800 mg imatinib.

The lack of a significant difference in such major clinical outcomes as progression-free survival and overall survival after only 31 months of follow-up (both >90%) was not surprising, but the study also failed to associate the higher dose with a significant improvement in CCyR, which was the primary end point. However, dose reductions on the higher dose were common.

“Although this study did not show a statistical benefit of 800 mg imatinib over 400 mg on ITT analysis, the patients who could comply with the higher dose did have a better cytogenetic outcome,” said Michele Baccarani, MD, an oncologist in the Department of Hematology and Oncological Sciences, University of Bologna, Italy. In pointed questions that followed his presentation, Dr. Baccarani acknowledged that it might be reasonable, despite these results, to start high-risk patients with CML on 800 mg of imatinib and then reduce the dose if it is not well tolerated.

Although Dr. Baccarani cautioned that he could not provide hard evidence from his study to support this approach, preliminary support for higher doses of imatinib could be drawn from the other studies, including a second study presented by Dr. Guilhot (abstract 183). This was a randomized comparison of three experimental arms with a reference arm of 400 mg imatinib daily in patients with newly diagnosed chronic-phase CML. The experimental arms were 400 mg imatinib daily, 600 mg imatinib daily, 400 mg imatinib in combination with ARA-C (20 mg/m2 per day on days 15-28 of a 28-day cycle), and 400 mg imatinib in combination with PEGIFN alfa-2a (90 mcg weekly). The four study groups were nearly equal in size with about 160 patients per arm.

In this study, there was an advantage at 12 months for the higher-dose imatinib as well as for both arms that included a

second agent. Specifically, CCyR climbed from 57% for imatinib 400 mg to 65% for imatinib 600 mg, 66% for imatinib plus ARA-C, and 71% for imatinib plus PEG-IFN. Relative to 400 mg imatinib, dose reductions due to adverse events also were more common for the alternative strategies, but the response advantages were achieved despite these dose reductions. Although longer follow-up is needed to verify that the greater cytogenetic responses translate into outcome advantages, Dr. Guilhot said a more aggressive approach appears promising.

The same conclusion was reached from a third multicenter study (abstract 184). Again, a series of experimental arms were compared with a standard of 400 mg imatinib in patients newly diagnosed with chronic-phase CML. In low- and intermediate-risk groups, the experimental arms included imatinib plus ARA-C, imatinib plus IFN and imatinib after IFN failure. There also was an arm of 800 mg imatinib daily evaluated in high-risk patients. The study was subsequently amended to randomize low- and intermediaterisk patients to 800 mg imatinib. As in the other studies that suggested better results can be achieved with intensification of therapy, the CCyR rates have been higher with higher imatinib doses and when imatinib is combined with another agent.

Lead author, Rüdiger Hehlmann, MD, University of Heidelberg, Mannheim, Germany, cautioned that the study is still randomizing patients and that data from the 800-mg imatinib arm are not yet fully evaluable. Still, he said that the projected five-year survival from those on intensified therapy is greater than 90%, which is better than that previously reported with standard doses of imatinib in such studies as IRIS. Dr. Hehlmann said that an “optimization of outcome is expected” with the newer therapeutic approaches. But he cautioned that response rates are surrogates and none of these strategies can be declared superior until a survival advantage has been demonstrated.

Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, Boston, who was not involved with the research, says that more studies are needed before drawing conclusions. “While a couple of the studies showed a higher response rate at 12 months, it may not be true that fastest is best,” he said. “Previous data has suggested that as long as you eventually got the response you were

Imatinib 800 mg Imatinib 400 mg

60

59

50

% of Patients

16

38

40 30 20 10 0

MMR

Figure. Comparison of patients with CML achieving a major molecular response in the TOPS trial.

CML, chronic myeloid leukemia; MMR, major molecular response; TOPS, Tyrosine Kinase dose Optimization Study

looking for, you did OK. The real question is not response but failure rates.”

Oncology Pharmacist’s Take Helen Marshall, PharmD, clinical pharmacist, Seattle Cancer Center Care Alliance, Wash., also stressed that the data for high-dose imatinib remain mixed. “But from the practical standpoint, increasing the dose of [the drug] before dismissing the therapy is a good option.”

However, “pharmacists are always focused on the toxicity of a regimen, and higher numbers of adverse events are reported with higher doses of imatinib and especially in combination with other traditional CML therapies.”

That higher frequency of adverse reactions “implies that closer monitoring and evaluation of medication adherence may be important issues in the management of patients on highdose imatinib,” she added. “The TOPS trial data is particularly interesting, suggesting that further studies need to establish a firm therapeutic range.

We think trough levels less than 1,000 ng/mL are correlated with decreased efficacy; however, establishing a desired or maximum peak level may be useful for adverse effect management.”

—Ted Bosworth

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18 Q & A

Pharmacy Practice News • October 2009

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Hem/Onc Pharmacy 19

Pharmacy Practice News • October 2009

In Focus

ODAC Vote Against Yondelis Dissected T

he FDA’s Oncologic Drugs Advisory Committee (ODAC) panel has voted 14 to 1 against approval for trabectedin (Yondelis, Centocor Ortho Biotech) in combination with doxorubicin hydrochloride liposome injection (DOXIL, Centocor Ortho Biotech) for the treatment of patients with relapsed ovarian cancer.

At the ODAC meeting, representatives of Centocor Ortho Biotech stated that the drug in combination with DOXIL increased progression-free survival (PFS) to six weeks. Citing concerns about toxicity and the methodology used in the registration trial, however, a vast majority of ODAC panelists voted against approval. The sole vote in favor of the combined therapy came from patient representative Martha Holland, of Southport, N.C. At the meeting, Wyndham Wilson, MD, head of the Lymphoma Therapeutics Section of the Metabolism Branch, Center for Cancer Research at the National Cancer Institute in Rockville, Md., summed up concerns about the drug. “My ‘no’ vote is not a no for this drug, but as other people have said, it is a no for the timing of this application,” Dr. Wilson said. “We are being asked to look at progressionfree survival after the study was originally written to look for overall survival.

And we’re being asked to accept a P value as predictive of a benefit. And I think that

Bevacizumab Approved for mRCC

T

he FDA has approved bevacizumab (Avastin, Genentech) plus interferon-alfa for the treatment of patients with metastatic renal cell carcin om a (mRCC) . The approval is based on data from a randomized, doubleblind, placebo-controlled Phase III study (AVOREN) of 649 patients with previously untreated mRCC. The study showed that median progression-free survival (PFS) was 10.2 months in patients who received bevacizumab plus interferon-alfa compared with 5.4 months in patients who received interferonalfa alone (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.490.72; P<0.0001). The independent review committee analysis of 569 patients with radiographs available for review yielded similar results (median PFS of 10.4 compared with 5.5 months; HR, 0.57; 95% CI, 0.45-0.72).

we’ve learned over the years that just because we have a small benefit—and I have no doubt that there is a benefit there—the real question is do we really have a significant benefit.”

Centocor Ortho Biotech Oncology Research & Development approached the FDA to open a new drug application for trabectedin in April 1996. In September 2004, the agency and applicant agreed to use overall survival as the end point for benefit analysis. However, in 2006, after 68% of the patients in the study were randomized, the applicant asked the FDA to switch the end point to PFS. John Seaman, PharmD, senior director of Regulatory Affairs at Centocor Ortho Biotech Oncology Research & Development, said the request to change the end point was made based on the FDA/ASCO/AACR end points workshop for ovarian cancer and subsequent to an approval of gemcitabine (Gemzar, Eli Lilly) and carboplatin for relapsed ovarian cancer patients after a trial demonstrating improvement in PFS. Panelist David P. Harrington, PhD, professor of biostatistics at Harvard School of Public Health, in Boston, called an end point shift after a trial starts “very rare.” He said that doing so creates “issues that don’t indicate that the sponsor did anything wrong, but that the data had a lot of weaknesses.”

Dr. Harrington said that using PFS as a

The study was originally designed to measure an improvement in overall survival (OS). However, in earlier consultation with the FDA and European regulatory authorities, the primary end point was changed to assess improvement in PFS. Secondary end points included objective response rate and OS. In this study, tumor size decreased in 30% of patients in the bevacizumab plus interferon-alfa group, compared with 12% of patients who received interferon-alfa alone.

There was no statistically significant improvement in OS based on the final analysis after 444 deaths.

The most common severe adverse events (grade 3 to 5) that occurred at a higher rate (at least 2% more often) in patients who received bevacizumab plus interferon-alfa than in the interferon-alfa only group included fatigue (13% vs. 8%), weakness (10% vs. 7%), protein in the urine (7% vs. 0), hypertension (6% vs. 1%) and bleeding (3% vs. 0.3%).

surrogate end point in cancer evaluation is complicated, because of the difficulties in measuring disease progression.

“If a sponsor is trying to get a sense of whether an agent works or a combination therapy works, progression-free survival can be a marker for whether or not a drug is active, but registration is a different sort of thing,” he said. “You’d like to put something on the label that is a reliable number that has been tested.”

Dr. Harrington noted that a ProgressionFree Survival Workshop organized by the Drug Information Association, FDA, National Cancer Institute, and Pharmaceutical Research and Manufacturers of America was slated to be held on Oct. 7-9, in Bethesda, Md. Panelist Gary H. Lyman, MD, MPH, a medical oncologist at Duke University in Durham, N.C., said he was concerned about toxicities reported in the trabectedin arm of the trial. “There was a fairly dramatic increase in grade 4 toxicities, and we were very concerned that the data was premature to recommend approval,” he said.

The FDA review of the trial revealed that grade 3 to 4 neutropenia was three times more frequent, febrile neutropenia was four times more frequent, and grade 3 to 4 thrombocytopenia was six times more frequent in the combination therapy arm. Among patients receiving trabectedin, six cases met Hy’s law cri-

Pemetrexed Approved For Fourth Indication

T

he FDA has approved pemetrexed for injection (Alimta, Eli Lilly) as maintenance therapy for locally advanced or metastatic non-small cell lung cancer (NSCLC), specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. The drug is not indicated for treatment of patients with squamous cell NSCLC. This is the fourth approval for the drug.

The drug was approved based on results from a multicenter, double-blind Phase III trial that compared efficacy with regard to overall survival of pemetrexed plus best supportive care (BSC) versus placebo plus BSC in 663 patients with stage IIIB/IV NSCLC, whose disease had not progressed after four cycles of platinum-based induction chemotherapy. The trial supported

teria for hepatic toxicity; no cases were seen in patients receiving the monotherapy. Cardiac events were three times as common in patients receiving trabectedin, and included six patients who had congestive heart failure. Dr. Lyman said that these potential risks, when paired with the questionable benefit offered by a trial with a shifting end point, left him with too many questions.

Now, the FDA must make a decision— it usually, but not always, follows the recommendations from ODAC. “We make a recommendation to the FDA, and they can take it or leave it,” Dr. Lyman said, “although with a 14-1 vote, it would be unusual for the FDA to move forward with a routine approval with the current information.”

Lisa Vaga, director of Oncology/Hematology Communications at Centocor Ortho Biotech, said the company still has hope for the drug. “Ovarian cancer is difficult to treat and the disease often recurs in patients who previously have been treated with platinum-based therapy, underscoring the need for nonplatinum treatment options,” she said.

“We continue to believe that trabectedin has an important role in the treatment of relapsed ovarian cancer. The company remains committed to working with the FDA to address the advisory committee’s concerns.”

—David Jakubiak

previous studies looking at the use of histopathology to tailor treatment for patients with advanced nonsquamous NSCLC. Patients in the trial were treated with pemetrexed (500 mg/m2 on day 1 of each 21-day cycle) or placebo, plus BSC. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Overall, pemetrexed increased progressionfree survival by almost two months (4.3 vs. 2.6 months; P<0.0001) and overall survival (OS) by almost three months (13.4 vs. 10.6 months; P=0.012). However, the relative benefits of pemetrexed maintenance were even greater in nonsquamous cell histologies. Although there was no OS advantage in the squamous cell tumors (9.9 vs. 10.8 months; P=0.678), the survival advantage exceeded five months (15.5 vs. 10.3; P=0.007; hazard ratio, 0.47; P<0.0001) when the squamous cell cancers were removed from the analysis.

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Important Limitations Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA.

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM serum sodium can be monitored closely oo rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable

Please see Important Safety Information on following page.

Š 2009 Otsuka America Pharmaceutical, Inc.

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IMPORTANT SAFETY INFORMATION FOR SAMSCA™ (tolvaptan) SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

SAMSCA is contraindicated in the following conditions: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae – During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. Subjects with serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the should generally be avoided.

Gastrointestinal Bleeding in Patients with Cirrhosis – Used only when the need to treat outweighs this risk Dehydration and Hypovolemia – In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in Co-administration with Hypertonic Saline – Not recommended CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors CYP 3A Inducers SAMSCA may need to be increased P-gp Inhibitors Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients levels Pregnancy and Nursing Mothers – SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother.

Commonly observed adverse reactions – (incidence ≥ and hyperglycemia (6% vs 1%)

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.

Reference: 1. Schrier RW, Gross P, Gheorghiade M, et al; SALT Investigators. Tolvaptan, a selective oral vasopressin V2 for hyponatremia. N Engl J Med

ß

Clinical 23

Pharmacy Practice News • October 2009

Pain Medicine

FDA: Botulinum Toxins Following New Safety Requirements F

our botulinum toxin products have complied with the FDA’s April 2009 directive to add boxed warnings to their labeling and develop Medication Guides, according to the agency. The new FDA mandate stems from reports of serious adverse events (AEs; e.g., potentially deadly swallowing and breathing difficulties, similar to the symptoms of botulism) when the toxin spreads from the injection site. At least one pain expert, however, thinks the move is unnecessary with regard to the use of botulinum toxin in the treatment of migraine.

The new labeling stresses that physicians should not view the four approved botulinum toxins as interchangeable because the measuring units differ from product to product. To help avoid future confusion and dispel the notion that these products can be substituted for each other, the four approved products also have changed their generic names.

Botox and Botox Cosmetic (Allergan) will now go under the generic name onabotulinumtoxinA; Myobloc (Solstice Neuroscience) will now be known as rimabotulinumtoxinB; and Dysport (Medicis and Ipsen)—which was approved in April 2009 under the new labeling and thus will not be making any changes—is now referred to as abobotulinumtoxinA. Brand names and formulations for all four products will remain the same.

Off-label uses that involve larger doses—such as the treatment of limb spasticity in patients with cerebral palsy (particularly children) or migraine relief—carry increased risks for AEs, according to the FDA. Public Citizen, a health advocacy group that petitioned the FDA to mandate the boxed warning, claims that the drug caused 180 serious AEs and 16 deaths in the United States as of early last year when it filed its report to the agency. According to the FDA, no serious cases of “distant spread of toxin effect” have been reported involving any of the on-label dermatologic uses of botulinum toxins, which are commonly used in low doses for cosmetic purposes and thus pose little danger to the patient.

Large Doses Not Needed “Migraine treatment does not require large doses,” commented Alexander Mauskop, MD, director of the New York Headache Center, New York City. “I do not think that there was any confusion between different types of toxin, and doctors are more likely to use brand names as they have done so far, not in the least because they are so much easier to pronounce. I am not aware of any substitution of one type of toxin for another, since it is well known to all physicians who inject that they are very

different from each other.”

In Dr. Mauskop’s opinion, the boxed warning is not necessary.

“You do have to have specialized training to inject Botox [botulinum toxins] and most doctors—perhaps excluding dermatologists, although they use small doses to begin with—are well familiar with these issues. I tell my patients that chances of dying are higher from NSAIDs [nonsteroidal anti-inflammatory drugs] or [acetaminophen] than from botulinum

toxin, which is confirmed by statistics.”

Botulinum toxin is not approved for the treatment of episodic or chronic migraine, but is commonly used by clinicians for this and other pain conditions. In 2008, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology issued an evidence-based review stating that botulinum toxin is “probably ineffective” in treating episodic migraine and chronic tension-

type headache, and that there is no strong evidence for its use in chronic daily headache. The group acknowledged, however, “clinicians’ practice may suggest stronger recommendations in some of these indications, [although] evidence-based conclusions are limited by the availability of data” (Neurology 2008;70:1707-1714; comment in Neurology 2009;72:1367; author reply 1367-1368).

—Seth Kandel and Donald M. Pizzi

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www.baxterbiosurgery.com GELFOAM PLUS Hemostasis Kit Indications GELFOAM PLUS is intended as a hemostatic device for surgical procedures when control of capillary, venous, and arteriolar bleeding by pressure, ligature, and other conventional procedures is either ineffective or impractical.

Thrombin (Human) used without the Gelfoam Sterile Sponge is not indicated for hemostasis.

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FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical.

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RX only: For safe and proper use of these devices, please refer to full device Instructions For Use. 1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data.

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BS1889 4/2008

24 Clinical

Pharmacy Practice News • October 2009

ACCP, ESC Latebreakers

Bivalirudin Scores in Anticoagulation Study Drug found superior to heparin plus GP IIb/IIIa Inhibitors In all patients, bivalirudin resulted in a nonsignificant 9% reduction in 30-day mortality, and a 15% reduction in oneyear mortality (P=0.048). The benefit of bivalirudin was even more pronounced in the 14,239 patients given guideline-recommended aspirin and clopidogrel prior to angiography or PCI. In these patients, bivalirudin resulted in a 26% reduction in 30-day mortality compared with treatment with heparin plus GP IIb/IIIa

Barcelona, Spain—Anticoagulation with bivalirudin monotherapy may be superior to dual therapy with heparin plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI). The treatment strategy resulted in a significant 15% reduction in mortality at one year, according to a meta-analysis of more than 18,000 patients presented at the 2009 Congress of the European Society of Cardiology (ESC).

Studies comparing bivalirudin (Angiomax, The Medicines Company) monotherapy to heparin plus GP IIb/IIIa inhibitors in patients with ischemic heart disease undergoing invasive management showed comparable suppression of ischemia with reduced bleeding with bivalirudin, according to investigator Gregg Stone, MD. But none of the individual studies was adequately powered for mortality, noted Dr. Stone, director of Cardiovascular Research and Education, New York-Presbyterian Hospital/Columbia University Medical Center, New York City.

The meta-analysis included three large randomized trials of bivalirudin versus heparin plus GP IIb/IIIa inhibitors: REPLACE-2 (Randomized Eval-

uation in PCI Linking Angiomax to Reduced Clinical Events), in patients with stable and unstable ischemic syndromes; ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), in patients with unstable angina and non-ST-elevation myocardial infarction; and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction), in ST-elevation MI.

Major adverse cardiac events and major bleeding at 30 days and one year were studied in the pooled analysis and mortality was assessed in all patients.

At 30 days, bivalirudin resulted in a significant 44% reduction in non-coronary artery bypass graft major bleeding compared with heparin plus GP IIb/IIIa inhibitors (P<0.0001). There was no significant difference in ischemia between the groups at 30 days and one year.

inhibitors (P=0.050), and a 20% reduction in one-year mortality (P= 0.02).

“In the U.S., the benefit of bivalirudin has been increasingly recognized, so that now a large percentage of patients undergoing PCI in the cath lab are treated with bivalirudin rather than heparin alone or heparin plus GP IIb/IIIa inhibitors. This trend should continue based on results of this pooled analysis,” Dr. Stone told Pharmacy Practice News. “The hope is

CANDIDIASIS

tially severe, infections,” Dr. Wang said.

The study included 103 neonates with IC and 58 controls. Neonates in both groups had a mean gestational age of 28 weeks, and 80% weighed less than 1,500 grams. The study found that use of H2 antagonists increased the risk for IC by 43%. The risk increased by 24% for babies undergoing GI/abdominal surgery, 17% in infants with congenital heart disease, and 2% in those receiving total parenteral nutrition. Length of hospital stay was significantly longer in the infants with IC (103 vs. 66 days). Of the babies with IC, 13 died, compared with only two deaths in the control group.

rates of IC, fluconazole prophylaxis may be considered for neonates whose birthweight is below 1000 g. (Clin Infect Dis 2009;48:503–535).

“With fungal prophylaxis, you always need to take into account the risk for breeding resistance, or side effects of the drugs,” said Toby Hoffman Cox, PharmD, BCPS, clinical specialist in pediatrics/neonatology and clinical assistant professor at the Medical University of South Carolina, Charleston.

“We don’t automatically put all babies under 1,000 g on fungal prophylaxis, but if we do a sepsis evaluation, and if they have risk factors for IC along with thrombocytopenia, we will add it.”

Dr. Hoffman said that in addition to the findings of the new study, another risk factor for IC is broad-spectrum antibiotic use (Pediatrics 2006;118:717722). “It changes the types of organisms the patients are colonized with,” she said. Dr. Hoffman added that the central venous lines required for premature babies can develop biofilms and cause infections. “We use a lot of central venous catheters for nutrition support in preemies and in babies who have had surgical procedures and cannot take enteral nutrition,” she said.

Steps can be taken to reduce the

continued from page 1

Invasive candidiasis (IC) has been reported to occur in 2% to 5% of very low birth-weight (<1,500 g) infants, noted Dr. Wang. The fungal infection may occur in infants with late-onset sepsis (>3 days of life) who are being managed in the neonatal intensive care unit (NICU). IC has been associated with significant morbidity and mortality.

‘We don’t automatically put all babies under 1,000 g on fungal prophylaxis, but if we do a sepsis evaluation, and if they have risk factors for IC along with thrombocytopenia, we will add it.’

— Toby Hoffman Cox, PharmD, BCPS “Premature babies have baseline morbidities which require many IV lines, which can lead to [IC] and other, poten-

‘The pharmacology and pharmacodynamics of bivalirudin offer a practical advantage [over] heparin and [GP IIb/IIIa] inhibitor combinations.’

—Amy Seybert, PharmD

An Early Start on Antibiotic Therapy “Starting antifungal therapy in neonates who develop signs and symptoms of candidiasis in the NICU with the above risk factors can be an option prior to obtaining a fungal culture,” Dr. Wang said. New clinical guidelines on candidiasis from the Infectious Disease Society of America (IDSA) recommend that neonates with IC receive a threeweek regimen of either amphotericinB or fluconazole. The guidelines also recommend that in nurseries with high

that presentation of these data at the ESC, and subsequent publication in a peerreviewed journal to come later this year, will lead to broader recognition of the importance of this pharmacologic regimen on an international basis.”

Pharmacist’s Perspective Commenting on the study for Pharmacy Practice News, Amy Seybert, PharmD, associate professor at the University of Pittsburgh School of Pharmacy, Pittsburgh, said the results confirms the safety advantage of bivalirudin by reducing bleeding in patients undergoing PCI. This outcome has been documented in previous individual studies.

“To my knowledge, this is the first mortality data [reported] with bivalirudin,” Dr. Seybert said. “The report offers interesting data on the mortality benefit in patients pretreated with clopidogrel.

The pharmacology and pharmacodynamics of bivalirudin offer a practical advantage [over] heparin and GP [IIb/ IIIa] inhibitor combinations.

“Further randomized trials and follow-up data from ongoing trials will be interesting and, potentially, can impact clinical practice further.”

—Fran Lowry

incidence of IC in the NICU, Dr. Cox said. “Hand hygiene is very important, as well as making sure not to overuse broad-spectrum antibiotics and H2 antagonists,” she said. Overuse of any medications that alter the patient’s normal gut flora could predispose them to developing infections with potentially harmful organisms such as Candida, Dr. Cox explained.

“We must also try to get intravenous catheters out as soon as possible.”

What the Guidelines Say IDSA guidelines note that failure to promptly remove or replace central venous catheters for infants with candidemia places the infant at increased risk for prolonged infection, mortality, and long-term irreversible neurodevelopmental impairment. Overuse of steroids also have been associated with fungal infections and should be used sparingly, Dr. Cox said.

She added that it is likely not congenital heart disease or GI/abdominal surgery themselves that lead to IC, but rather the support that these infants must receive. “They need parenteral nutrition or antibiotics and central venous lines,” she said.

—Celia Vimont

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26 Clinical

Pharmacy Practice News • October 2009

Pain Medicine

Pain Experts Review Recent FDA Moves

O

ver the past nine months, the FDA has taken several steps regarding prescription and nonprescription painkillers that have the potential to dramatically affect how physicians treat pain. The agency has rejected drug applications for “abuse–deterrent” opioid products while calling for aggressive changes to the warning labels of nearly two dozen opioids in an effort to stem abuse of these drugs. The FDA appears poised to pull from the market two widely used analgesics, Vicodin and Percocet, because the products contain acetaminophen—a drug that has come under increased scrutiny in recent months for its potential for liver toxicity. The agency also banned several unbranded opioids, then partially reversed itself when faced with an outcry from patients and clinicians.

Given the FDA’s concern about the safety and abuse potential of pain products— some experts believe the agency would reject aspirin were it to be submitted as a new drug for approval today—the editors of Pharmacy Practice News, Pain Medicine News and Anesthesiology News solicited the opinions of pharmacy, pain and addiction experts to address the FDA’s actions.

Q

: Is the FDA justified in its recent actions regarding opioids and nonopioid pain medications?

Steven D. Passik, PhD: The use of the word “justified” is interesting. Sure, [the agency is] justified. I mean, they are newly empowered by the FDAAA (Food and Drug Administration Amendments Act), and they have the authority. All of this is in response to public outcry and pressure from Congress regarding prescription drug abuse, which is a huge problem. The question is, if given the pressure they are feeling to act, are they doing the right thing? I guess that is a separate question, but yeah, they are justified.

Arthur Lipman, PharmD: I would agree that the FDA is empowered to help ensure the safe use of prescription pain medications. But are the agency’s recent actions justified? That indeed is a different question. The FDA advisory committee’s recommendation, for example, to remove all combination opioid–acetaminophen products from the market is ill conceived. As the American Pain Foundation recently pointed out, such an outright ban is far too over-reaching and, if enacted, could harm the millions of chronic pain patients who rely on these drugs for effective pain management.

The FDA would be far wiser to ban highdose acetaminophen-containing opioid formulations. Basically, anything over 325 mg is usually overkill and most likely causing the lion’s share of liver toxicity.

What the FDA is not empowered to do, unfortunately, is to amend the legislative underpinnings that have enabled these high-dose opioid–acetaminophen combinations to proliferate. One cause is the Controlled Substances Act of 1970, which classifies hydrocodone, in combination with nonopioids, as a Schedule III controlled substance. It’s the only drug that is scheduled by the Act wherein it is mentioned by its chemical (not generic) name, and certainly is the only strong opioid not to be classified as a Schedule II controlled substance. As a result, it has become the No. 1-prescribed prescription analgesic in the United States, in large part because prescriptions for it can be telephoned in to a pharmacy, it can be refilled, and physicians don’t have to deal with the scrutiny they might get over Schedule II medications.

The other cause of this proliferation is not so much a specific piece of leg-

islation as it is the lack of one. In Great Britain, if a company tries to market a “me-too” drug such as a combination opioid formulation that simply has a boosted acetaminophen dose, it won’t get approved because it has no demonstrable advantage over existing formulations. In the U.S. system, in contrast, a pharmaceutical company can introduce a medication that is clearly inferior to what is already available. As long as it’s safe and effective within the labeling, the FDA does not have the legal authority to preclude it from being approved.

I realize the FDA’s recent proposals are not limited to banning opioid–acetaminophen combinations. But the ban does illustrate the political and economic constraints under which we are operating, that put a ceiling on just how much we can protect our chronic pain patients.

Marv Seppala, MD: The system itself is very troublesome. While I do think some things need to be done to better address the problems of prescription medication abuse, I don’t know if these efforts by the FDA are the right way to go. Physicians need the freedom to practice as they see fit.

Clifford Gevirtz, MD, MPH: I believe the FDA is undertaking a major change in how analgesia is dispensed in this country. Although some of the agency’s actions may be grounded in evidence, it clearly is effectively rewriting pain guidelines with minimal input from stakeholders. For example, the American Geriatrics Society (AGS) wants to replace nonsteroidal anti-inflammatory drugs (NSAIDs) with opiates as first-line analgesics. Presumably, drugs such as Vicodin and Percocet were to be the mainstay of geriatric analgesia; whoops, I guess it’s back to the drawing board for the AGS. In contrast, the World Health Organization’s analgesic ladder, which is evidence-based in both cost and clinical effectiveness, needs a few rungs recast, according to the FDA.

Q

: Will the FDA’s approach improve patient safety?

Dr. Passik: I think it’s unpredictable at this point. Part of the problem is that there are no clearly measurable outcomes. As a pain clinician, I don’t see anything on the table that will help pain clinicians with regard to the complex

EXPERT PANEL Clifford Gevirtz, MD, MPH is medical director of Metro Pain Management and Addiction Recovery Institute in New Rochelle, N.Y. He is a member of the editorial board of Anesthesiology News.

decisions they have to make in terms of pain treatment, drug abuse and diversion. What I see is a lot of proposals that will likely limit prescribing. And if a drop-off in prescribing occurs, it stands to reason that there will be a drop-off in nonmedical use. And those in power will claim victory; those treating pain will find it harder to do so; and those in pain will find it more difficult to get relief.

Dr. Seppala: The motivation to get the drug on the part of the addict is better than any motivation to stop it. You can’t undermine optimal care by putting in systems that are onerous and not that helpful. What we need to focus on and look at is how we can treat addiction better.

Arthur G. Lipman, PharmD, FASHP is professor of pharmacotherapy, College of Pharmacy; and director of clinical pharmacology, Pain Management Center, University of Utah Health Sciences Center, Salt Lake City. Dr. Lipman is also the editor of the Journal of Pain & Palliative Care Pharmacotherapy.

Q

: What are your views on the FDA’s handling of acetaminophen labeling and maximum dosing?

Dr. Gevirtz: There have been several studies done, pointing to the fact that there is little added benefit beyond certain doses of acetaminophen. For example, a study by Toms et al examined the efficacy of single-dose oral acetaminophen for the treatment of acute postoperative pain. They searched The Cochrane Library, PubMed, EMBASE, the Oxford Pain Relief Database and reference lists of articles selecting only randomized, double-blind, placebo-controlled clinical trials of acetaminophen for acute postoperative pain in adults (Cochrane Database Syst Rev. 2008;8:CD004602).

Two review authors independently assessed trial quality and extracted data. Area under the curve for “pain relief versus time” was used to derive the proportion of participants with acetaminophen or placebo experiencing at least 50% pain relief over four to six hours, using validated equations.

The researchers calculated NNT, with 95% confidence intervals. The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals also was collected. The researchers found 51 studies, with 5,762 participants, that met their entry criteria. A total of 3,277 patients were treated with a single oral dose of acetaminophen and 2,425 with placebo. Approximately half of participants treated with acetaminophen at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo.

The NNTs for at least 50% pain relief over 4 to 6 hours following a single dose of acetaminophen were as follows: 500 mg, NNT 3.5 (2.7-4.8); 600 to 650 mg, NNT 4.6 (3.9-5.5); 975 to 1,000 mg, NNT 3.6 (3.4-4.0). The important finding was that there was no clear additive dose– response between 500 and 1,000 mg.

So although the the FDA is trying to prevent liver toxicity [with its dosage limits or outright product bans], it may be throwing the baby out with the bath water; standard acetaminophen doses appear to be both safe and effective.

Steven D. Passik, PhD is associate attending psychologist at Memorial Sloan-Kettering Cancer Center; and associate professor of psychiatry, Weill Cornell Medical College, both in New York City.

Marv Seppala, MD is chief medical officer of the famed Minnesotabased substance abuse treatment center Hazelden. One of the first physicians in the United States certified by the American Board of Addiction Medicine, Dr. Seppala is himself a recovering addict.

Dr. Lipman: The lack of any additive dose response beyond 500 mg in the Toms et al [literature review] dovetails with clinical experience. And even though those studies looked at acetaminophen versus placebo, they do point to what would be an effective dose for combination products. In fact, I would posit that even 325 mg of acetaminophen in such formulations would suffice for the majority of pain patients. That dosage, along with 5 or 10 mg of oxycodone, worked great for a lot of years as straight Percocet. And people took one or two of those. There was never a need for 650/5 or 650/10 mg formulations.

Q

: If the FDA continues down its current path, how will future pain therapy be affected?

Dr. Passik: There are two things on the table relative to that. One is certification

•

see PAIN EXPERTS, page 40

Clinical 27

Pharmacy Practice News • October 2009

Pain Medicine

Urine Testing May Reveal Problems With Opioid Therapy N The data ‘clearly [show] the

early 40% of all patients who were prescribed opioids for chronic pain and then screened via urine testing had no detectable levels of the drug present, according to a new study. The most likely explanations for the missing medications—noncompliance and drug diversion—underscore the importance of administering periodic urine drug tests (UDT) in this patient population, the researchers concluded.

A Huge Data Set Investigators from the Jefferson School of Population Health at Thomas Jefferson University in Philadelphia, and Ameritox, the company that conducted the UDT study, looked to determine the prevalence of noncompliance, and potential abuse and diversion, in a population of chronic pain patients who were prescribed opioids. To that end, the researchers collected data from 943,776 patient samples (520,770 female; 422,750 male; 256 gender unknown).

Urine samples used in the study were collected between January 2006 and September 2008 during routine pain clinic visits.

The researchers found that in 39% of the patients, physicians indicated that the subjects were taking a chronic opioid, “yet the drug was not present in the patients’ bodies,” said investigator Harry L. Leider, MD. The finding suggest that these patients “could be hoarding [their opioids], or mistakes in record-keeping were made. But a substantial amount of this was likely due to diversion.”

Dr. Leider pointed to another “startling” result: 11% of the urine samples in the study tested positive for major illicit drugs “which is higher than SAMHSA [Substance Abuse and Mental Health Services Administration] data,” he said.

“And these are chronic pain patients who know they might get tested.”

Unprescribed opioids were found in 29% of the urine samples. “In these cases, where we found a controlled substance the doc didn’t know about, it could be that another doctor prescribed it,” said Dr. Leider, “or it could be off the street.”

Drug levels were higher than expected in 27% of noncompliant patients and lower than anticipated in 15%. Few demographic differences existed with regard to inappropriate drug-taking behavior, although individuals in the 36- to 50-year age group were 30% more likely than those younger than age 21 to have samples absent of their prescribed medication.

There were no significant differences between the men and women in terms of noncompliance outside of illicit drug use, with 14.6% of men testing positive

compared with 8.6% of women. Illicit drug use also was significantly more common in younger individuals, with 16.8% of patients under the age of 21 and 17.2% of those between the ages of 21 and 35 testing positive, compared with 13.3% of 36- to 50-year-olds, 8.3% of those between the ages of 51 and 65 and 1.6% of seniors (aged ≥65).

“These … results … demonstrate a significant clinical concern and confirm the importance of periodic urine drug screening for the population prescribed long-term opioid therapy,” wrote the study authors.

The researchers acknowledged certain limitations of the study, including selection bias—tests are more likely ordered for patients when physicians expect abuse or other irregularities (reasons for testing were not reported in the study). Patient actions, such as delaying testing to allow drugs to clear

their system, also could have affected the results, according to the investigators. Univariate and bivariate analyses also limited study data.

Despite those limitations, “the size of the study sample speaks to the strength of the data,” Dr. Leider said. “The study included 700,000 patients and nearly 1 million data points.” The breadth of the evidence, he stressed, “clearly [show] the degree to which patients are—or are not— taking their medications as prescribed.”

The tests screened for opiates, benzodiazepines, illicit drugs and other agents through the use of enzyme immunoassay or fluorescence polarization immunoassay. Positive immunoassays were confirmed using gas chromatography-mass spectrometry or liquid chromatography-tandem mass spectrometry. The samples were then scrutinized during a second phase using a proprietary methodology “and then

One “startling” result: 11% of the urine samples in the study tested positive for illicit drugs.

degree to which patients are— or are not—taking their [chronic pain] medications.”

—Harry L. Leider, MD compared with expected ‘ranges’ that we derived from patients taking the prescribed medication correctly—that is, at the specified dose and frequency,” Dr. Leider explained.

He added that by repeating a test and finding levels to be consistent, the testing process can determine which patients have abnormal results because they are simply slow metabolizers.

Significance Questioned “Medication compliance with any prescription drug is always a problem for all patients, and it is not surprising that the study found this in this population,” said David S. Craig, PharmD, BCPS, a clinical pharmacist specialist and residency director of psychosocial, palliative care and integrative medicine at Moffitt Cancer Center, Tampa, Fla. He acknowledged that both routine and random urine drug screening are of some—“but limited”—clinical utility.

“But what I find is that it often gives nonspecialists a false sense of security because these tests have a significant amount of limitations and they are often misunderstood and misused,” he said.

Steven Passik, PhD, associate attending psychologist at Memorial SloanKettering Cancer Center and associate professor of psychiatry at Weill Cornell Medical College, both in New York City, offered another pain specialist’s take on urine drug testing.

“It is a bona fide problem when illicit drugs are found; it is a bona fide problem when nonprescribed drugs are found; and it is a bona fide problem when none of the prescribed drugs are found,” Dr. Passik said. “However, the methods for determining less or more of the prescribed drugs are still undergoing validation” in clinical studies.

Some of those studies “have yielded encouraging data about drug testing’s potential accuracy,” added Dr. Passik, who has served on scientific and clinical advisory boards for Ameritox.

The UDT study results were published in Population Health Management (2009;12:185-190). Funding for the study was provided to the Jefferson School of Population Health by Ameritox.

—Donald M. Pizzi

28 Clinical

Pharmacy Practice News • October 2009

Pain Medicine

Analgesic Toxicity Drives Mortality After Lumbar Fusion M ore than 20% of deaths reported in a new study of mortality associated with lumbar fusion surgery were related to analgesia poisoning, with individuals with degenerative disc disease (DDD) and those undergoing repeat procedures at increased risk for analgesic-related death following the surgery.

The absolute risk for an analgesicrelated death among patients undergoing the procedure was nearly 1%, researchers found. Most of the deaths occurred months or years after surgery.

The extended time frame of risk seen in these patients is a concern, noted Julie Golembiewski, PharmD, clinical associate professor of pharmacy practice at University of Illinois Medical Center, in Chicago. “It appears that the problem is months or longer after the surgery, especially if an orthopedic surgeon is managing their opioid use,” she said. “I don’t know if pharmacists in the community would even know how to look out for this or determine if opioid adjustments are appropriate post-op. We have the opposite problem—surgeons and primary care physicians who won’t prescribe a CII [Schedule II] opioid for a patient who really needs it. We get those patients in our pain clinic and have a very hard time sending them back to the [primary care physician]. They don’t want to prescribe CIIs.”

Study Detailed Lumbar fusion–related death is generally considered to be a rare occurrence (Spine 2005;30:1441-1445). In an attempt to determine the incidence and causes of mortality following the spinal surgery, investigators analyzed Washington state workers’ compensation claims of patients with back pain who underwent the procedure between January 1994 and December 2001. The researchers, who published their findings in Spine (2009;34:740-747), listed the population-based design and the fact that it was not limited to one health care system or clinical practice as strengths of the study.

By 2004, 103 of the 2,378 patients undergoing lumbar fusion surgery had died. Researchers observed a perioperative mortality rate at 90 days of 0.29% (95% confidence interval [CI], 0.11%0.60%) and a three-year cumulative mortality rate of 1.93% (95% CI, 1.41%2.57%). After adjusting for age and sex, all-cause mortality occurred at a rate of 3.1 per 1,000 worker-years (95% CI, 0.99.8). Death was more common in patients undergoing repeat lumbar fusion.

The most common cause of death was analgesic poisoning (n=22; 21%), described as accidental in 19 cases and

related to suicide in three other cases. Twenty of these analgesic-related fatalities involved opioids, whereas two were due to nonopioid analgesics. Other causes of death included cancer (n=19), heart disease (n=15), chronic lower pulmonary disease (n=7) and suicide (n=6).

The investigators described 26 deaths as accidental.

Analgesic-related mortality occurred only in cases involving instrumentation or intervertebral cage devices (1.1%);

in contrast, fusions that involved only bone were not linked to any deaths related to analgesia use (P=0.03; ageand sex-controlled, P=0.01). Patients whose deaths were related to analgesic use tended to be younger (44.8 years on average, compared with 54 years for all other causes; P<0.001).

The only specific diagnosis linked to an increased risk for analgesic-related mortality was DDD, which was diagnosed in 10 of the 22 patients whose

deaths were described as analgesicrelated (rate ratio, 2.71, adjusted for age and sex; 95% CI, 1.17-6.28). The link between DDD and analgesic-related death was especially strong in middleaged patients (45-54 years; rate ratio, 7.45; P=0.01).

“The finding that 45% of workers who died of analgesic-related death had DDD implies that attention should focus initially on patients with DDD for the development of interventions

Myth: Sugar and spice make everything nice

Clinical 29

Pharmacy Practice News • October 2009

Pain Medicine “We really don’t know whether instrumentive fusions work any better,” said David Kloth, MD, a pain medicine and management physician in Danbury, Conn. “But what we do know is that wh en th ere are adverse events, they can be much more serious.”

to minimize analgesic-related deaths,” according to the researchers, led by Sham Maghout Juratli, MD, assistant professor of family medicine at Wayne State University School of Medicine in Detroit, Mich.

The use of surgical devices in lumbar fusion has increased significantly over the past 20 years. The authors point out that the increased use of such devices has not resulted in decreased work disability, repeat fusion rates or postoperative complications, but is now linked to higher rates of analgesicrelated deaths.

‘Not a 100% Success Rate’ Dr. Juratli said the results must be tempered by the fact that there was no control group in the study. Still, “the finding that analgesic-related death was the leading cause of death after lumbar fusion— which is primarily and increasingly performed to treat pain from degenerative back disease—may signal the lack of effectiveness of this procedure in treating chronic degenerative back pain.”

The results did not surprise Dr. Kloth, who said that aggressive surgeries such as lumbar fusion “do not always have the most stellar outcomes.”

...dispelled by science Sugar and spice may make everything nice in fairy tales. In intravenous (IV) iron therapy, however, distinctions between iron carbohydrate complexes can be significant. Venofer ® (iron sucrose injection, USP) 1 and Ferrlecit ® (sodium ferric gluconate complex in sucrose injection) 2 are often referred to as 2nd generation or non-dextran containing IV irons. Dexferrum ® (iron

the latest entry approved on June 30, 2009. While Feraheme™ can be administered at high doses rapidly, making it potentially very convenient, further experience with this product may be prudent, especially in patients with a history of multiple drug allergies or in patients intolerant to other IV iron products.9,10

®

Reality: Only Venofer has a distinctive iron sucrose formula that has a demonstrated safety profile proven in both pre-dialysis and dialysis patients, as well as in hemodialysis patients with prior intolerance to iron dextran, ferric gluconate, or both.1 dextran injection, USP) 3 and INFeD ® (iron dextran injection, USP) 4 are sometimes referred to as 1st generation IV irons and contain unmodified dextran. The latest IV iron entry, Feraheme™ (ferumoxytol) injection, is patented as a “reduced” dextran, or, dextran derivative.* 5

Consider the Carb Why categorize? While the 1st and 2nd generation IV iron therapies have long histories of demonstrated efficacy, non-dextran and dextran containing IV iron complexes have distinctly different histories of safety and tolerability.

Lessons of History Iron dextran was the first IV iron compound to be licensed, and at one time, iron dextran products were the most widely used. 6,7 However, their use declined significantly as clinicians became more and more concerned about the risk of severe reactions, especially life-threatening anaphylaxis.6,8 This concern regarding dextrans still persists today. Enter Feraheme™,

A Proven Choice Venofer ®, however, is a clinically proven IV iron therapy with a long history of demonstrated safety and tolerability in clinical practice, even in hemodialysis patients intolerant to other parenteral irons.1 In pre-dialysis studies, Venofer ® was well tolerated and more effective than oral iron. A course of therapy increased hemoglobin levels and improved adequacy of iron for erythropoiesis with fewer gastrointestinal side effects than oral iron.11,12 Unlike IV iron dextrans and dextran derivatives, Venofer ® does not require an observational period; nor does its labeling require having personnel or therapies readily available for the treatment of hypersensitivity reactions.

Making it one sweet choice for CKD patients where IV iron therapy is appropriate.

In reality, when IV iron therapy is prudent, you can never be too safe or too confident. But you can prescribe Venofer ®.

IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving IV iron, and has also been reported in non-dialysis dependent (NDD) and peritoneal dialysis dependent (PDD)-CKD patients receiving IV iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose delivered.

In multi-dose efficacy studies in HDD-CKD patients (N=231), the most frequent adverse events (>5%), whether or not related to Venofer® administration, were hypotension, muscle cramps, nausea, headache, graft complications, vomiting, dizziness, hypertension, chest pain, and diarrhea. In post-marketing safety studies in HDD-CKD patients (N=1051), the most frequent adverse events reported (>1%), whether or not related to Venofer® administration, were congestive heart failure, sepsis, and taste disturbance. In multi-dose efficacy studies in NDD-CKD patients (N=91), the most frequent adverse events ( 5%), whether or not related to Venofer® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension. In the study of PDD-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer®, reported by 5% of these patients were diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis, peripheral edema, and nausea. *No detectable unmodified dextran.

Note: Dexferrum is a registered trademark of American Regent, Inc. Feraheme is a trademark of AMAG Pharmaceuticals, Inc. Ferrlecit is a registered trademark of A. Nattermann & CIE. GMbH. INFeD is a registered trademark of Watson Pharma, Inc. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

Millions prescribed. Millions treated.

™

Leading anemia management.™

Please see brief prescribing information and references on adjacent page.

VMvR1 Iss. 8/2009

According to Dr. Kloth, who is the founder, medical director and president of Connecticut Pain Care, the high rate of analgesic-related mortality seen in this study is something to be expected in workers’ compensation patients.

“It is a population that tends to not do very well [with fusion surgery],” he said.

“They don’t get back to work and have higher rates of depression, all kinds of social issues that affect their recovery and increased suicidal thoughts.”

Dr. Kloth said he was interested in finding out if pain specialists or surgeons

•

see TOXICITY, page 30

30 Clinical

Pharmacy Practice News • October 2009

Pain Medicine

IV Acetaminophen Looks Safe for Children Phoenix—Repeated doses of intravenous acetaminophen appear to be safe in pediatric surgery patients, including newborns, new data suggest.

IV acetaminophen (IV APAP) is among the more widely administered pain relievers in the world. The drug is available in nearly 70 countries for the treatment of acute pain and fever, although it is not yet on the market in the United States.

The new data come from two multicenter clinical trials sponsored by

Cadence Pharmaceuticals, which hopes to win FDA approval for its IV APAP product, Acetavance. The studies included a five-day safety trial involving 100 pediatric inpatients, and a 48-hour pharmacokinetic and safety analysis in which 75 pediatric inpatients received the treatment. Children in the studies ranged in age from full-term neonates to teenagers.

In the five-day trial, patients were given doses of IV APAP based on weight (10-15 mg/kg), at the discretion of the

treating clinician. For the pharmacokinetic study, children were randomized to receive either 12.5 or 15 mg/kg, the researchers said.

IV APAP was well tolerated in both trials, with no serious adverse reactions considered to be certainly or probably related to the drug, reported the investigators, led by Elliott J. Krane, MD, professor of anesthesia and pediatrics at Stanford University School of Medicine in Stanford, Calif. Overall, six children

References: 1. Venofer® [package insert]. Shirley, NY: American Regent, Inc.; 2008. 2. Ferrlecit® [package insert]. Corona, CA: Watson Pharmaceuticals, Inc. Rev. 9/06. 3. Dexferrum® [package insert]. Shirley, NY: American Regent, Inc. Rev. 11/05. 4. INFeD® [package insert]. Morristown, NJ: Watson Pharma, Inc. Rev. 03/06. 5. Groman EV, Paul KG, Frigo TB, Bengele H, Lewis JM, inventors; Advanced Magnetics Inc., assignee. Heat stable colloidal iron oxides coated with reduced carbohydrates and carbohydrate derivatives. US Patent 6 599 498. July 29, 2003. 6. Auerbach M. Ferumoxytol as a new, safer, easier-toadminister intravenous iron: yes or no? Am J Kidney Dis. 2008;52:826-829. 7. Macdougall IC, Ashenden M. Current and upcoming erythropoiesis-stimulating agents, iron products, and other novel anemia medications. Adv Chronic Kidney Dis. 2009;16:117-130. 8. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004;19:1571–1575. 9. Feraheme™ [package insert]. Lexington, MA: AMAG Pharmaceuticals, Inc. 06/09. 10. Coyne DW. Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease. Expert Opin Pharmacother. 2009;10(15): 1-6. 11. Charytan C, Qunibi W, Bailie GR, and the Venofer Clinical Studies Group. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract. 2005;100(3):c55-c62. 12. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856.

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection,USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin

(Table 2 continued)

Adverse Events (Preferred Term)

(Table 3 continued)

NDD-CKD Venofer® Oral Iron (N=139) (N=139) % %

Adverse Events (Preferred Term)

NDD-CKD 200 mg 500 mg (N=109) (N=30) % %

Musculoskeletal and Connective Tissue Disorders Musculoskeletal and Connective Tissue Disorders CONTRAINDICATIONS Pain in extremity 4.6 3.3 2.2 3.6 The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients Back pain Nervous System Disorders Muscle cramp 0.7 0.7 with anemia not caused by iron deficiency.

Dizziness 5.5 10.0 Myalgia 3.6 0 WARNINGS Headache 3.7 0 Pain in extremity 4.3 0 Hypersensitivity reactions have been reported with injectable iron products.See PRECAUTIONS and ADVERSE REACTIONS. Respiratory, Thoracic and Mediastinal Disorders PRECAUTIONS Nervous System Disorders Cough 0.9 6.7 General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of Dizziness 6.5 1.4 tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin Headache Dyspnea 1.8 10.0 2.9 0.7 saturation). Iron therapy should be withheld in patients with evidence of iron overload.Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum Pharyngitis 0 0 Hypoesthesia 0.7 0.7 iron values may be reliably obtained 48 hours after IV dosing.See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Skin and Subcutaneous Tissue Disorders Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the Respiratory, Thoracic and Mediastinal Disorders Pruritus 0.9 6.7 2.2 0.7 clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening Cough Vascular Disorders Dyspnea 3.6 0.7 hypersensitivity reactions in patients receiving Venofer.See ADVERSE REACTIONS. Hypertension NOS 6.4 6.7 Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in Dyspnea exacerbated 2.2 0.7 Hypotension NOS 0.9 6.7 non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related Nasal congestion 1.4 2.2 to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Pharyngitis 0 0 *NOS=Not otherwise specified Carcinogenesis,Mutagenesis,and Impairment of Fertility: Rhinitis allergic NOS 0.7 2.2 No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®.

Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse Skin and Subcutaneous Tissue Disorders Pruritus 2.2 4.3 micronucleus test.

1.4 2.2 Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and Rash NOS Vascular Disorders reproductive performance of male and female rats.

6.5 4.3 Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body Hypertension NOS surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no Hypotension NOS 2.2 0.7 evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction *NOS=Not otherwise specified studies are not always predictive of human response,this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Venofer® is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. be exercised when Venofer® is administered to a nursing woman. ® ® Pediatric Use: Safety and effectiveness of Venofer in pediatric patients have not been established. In a country where Venofer is available for use in children, at a single site, five Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population) premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other NDD-CKD medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs Adverse Events 200 mg 500 mg could be established.

(Preferred Term) (N=109) (N=30) Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger % % subjects.No overall differences in safety were observed between these subjects and younger subjects,and other reported clinical experience has not identified differences in responses Subjects with any adverse event 23.9 20.0 between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out.

Gastrointestinal Disorders ADVERSE REACTIONS Diarrhea NOS* 0 0 Adverse Events observed in all treated populations Dysgeusia 7.3 3.3 The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis Nausea 2.8 0 dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 General Disorders and Administration Site Conditions patients. In addition,over 2,000 patients treated with Venofer® have been reported in the medical literature.

Infusion site burning 3.7 0 Treatment-emergent adverse events reported in 2% of patients by dose group Treatment-emergent adverse events reported by 2% of treated patients with Injection site pain 2.8 0 ® are shown in Table 3.

NDD-CKD in the randomized clinical trials, whether or not related to Venofer Peripheral edema 1.8 6.7 administration, are listed by indication in Table 2.

Nervous System Disorders Table 3. Most Common Treatment-Emergent Adverse Events Table 2. Most Common Treatment-Emergent Adverse Events Reported Dizziness 2.8 6.7 Reported in 2% of Patients with NDD-CKD by Dose Group in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Headache 2.8 0 (Multidose Safety Population) Safety Population) Vascular Disorders Hypotension NOS 0 6.7 NDD-CKD NDD-CKD Adverse Events Venofer® Oral Iron Adverse Events 200 mg 500 mg *NOS=Not otherwise specified (Preferred Term) (N=139) (N=139) (Preferred Term) (N=109) (N=30) Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients % % % % In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer®, reported by 5% of the Venofer® exposed patients Subjects with any adverse event 76.3 73.4 Subjects with any adverse event 75.2 80.0 were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related Ear and Labyrinth Disorders Ear and Labyrinth Disorders adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic Ear Pain 2.2 0.7 Ear Pain 0.9 6.7 reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group),three Venofer® patients had events that were considered drug-related (hypotension,dyspnea and nausea).

Eye Disorders Eye Disorders Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. Conjunctivitis 0 0 Conjunctivitis 0 0 In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension Gastrointestinal Disorders Gastrointestinal Disorders occurred in 2 patients treated with Venofer® at a dose of 500 mg.

Abdominal pain NOS* 1.4 2.9 Abdominal pain NOS* 1.8 0 The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or Constipation 4.3 12.9 Constipation 3.7 6.7 collapse,bronchospasm with dyspnea,or convulsion) associated with Venofer® administration.

Diarrhea NOS 7.2 10.1 Diarrhea NOS 6.4 10.0 OVERDOSAGE Dysgeusia 7.9 0 Dysgeusia 9.2 3.3 Dosages of Venofer® (iron sucrose injection,USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis.Periodic monitoring of iron parameters Nausea 8.6 12.2 Nausea 9.2 6.7 such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be Vomiting NOS 5.0 8.6 Vomiting NOS 5.5 3.3 discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment General Disorders and General Disorders and has been incorrectly diagnosed as iron deficiency anemia.

Administration Site Conditions Administration Site Conditions Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as Asthenia 0.7 2.2 Asthenia 0.9 0 recommended or at a slower rate may also alleviate symptoms.

Chest pain 1.4 0 Chest pain 0.9 3.3 Preclinical Data: Edema NOS 6.5 6.5 Edema NOS 7.3 3.3 Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and Fatigue 3.6 5.8 Fatigue 4.6 0 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal.

Feeling abnormal 0 0 Feeling abnormal 0 0 The symptoms of acute toxicity were sedation,hypoactivity,pale eyes,and bleeding in the gastrointestinal tract and lungs.

Infusion site burning 3.6 0 Infusion site burning 3.7 3.3 DOSAGE AND ADMINISTRATION Injection site extravasation 2.2 0 Injection site pain 2.8 0 The dosage of Venofer® is expressed in terms of mg of elemental iron.Each mL contains 20 mg of elemental iron.

Injection site pain 2.2 0 Peripheral edema 5.5 13.3 Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin Peripheral edema 7.2 5.0 Pyrexia 0.9 0 response and to replenish iron stores (ferritin,TSAT).

Pyrexia 0.7 0.7 Infections and Infestations Administration:Venofer® must only be administered intravenously either by slow injection or by infusion.

Infections and Infestations Catheter site infection 0 0 Recommended Adult Dosage: Catheter site infection 0 0 Nasopharyngitis 0.9 0 Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period.There is limited experience with administration of an infusion of 500 mg of Venofer®,diluted in a maximum Peritoneal infection 0 0 Sinusitis NOS 0 3.3 of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS,Study D: Non-Dialysis DependentSinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.9 0 Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.)

Upper respiratory tract infection NOS 0.7 1.4 Injury, Poisoning and Procedural Complications HOW SUPPLIED Graft complication 1.8 0 Urinary tract infection NOS 0.7 5.0 Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 Injury, Poisoning and Procedural Complications Investigations mg/mL).Contains no preservatives.Store in original carton at 25°C (77°F).Excursions permitted to 15°-30°C (59°-86°F).[See the USP controlled room temperature]. Do not freeze.

Graft complication 1.4 0 Cardiac murmur NOS 2.8 0 Sterile Fecal occult blood positive 1.8 0 Investigations NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed Cardiac murmur NOS 2.2 2.2 Metabolism and Nutrition Disorders NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 Fecal occult blood positive 1.4 3.6 Fluid overload 1.8 0 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Gout 1.8 6.7 Metabolism and Nutrition Disorders Rx Only Hyperglycemia NOS 3.7 0 Fluid overload 1.4 0.7 [1] National Kidney Foundation.

K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. REFERENCE: Hypoglycemia NOS 0.9 0 Gout 2.9 1.4 37:S182-S238,(suppl 1) 2001.

Hyperglycemia NOS 2.9 0 Musculoskeletal and Connective Tissue Disorders Hypoglycemia NOS 0.7 0.7 Arthralgia 0.9 3.3 Back pain 1.8 3.3 Musculoskeletal and Connective Tissue Disorders BS2340 VMvR1 Muscle cramp 0 3.3 Arthralgia 1.4 2.2 Rev.10/08 Iss.8/2009 Myalgia 2.8 6.7 Arthritis NOS 0 0 © 2009 American Regent,Inc Venofer® is manufactured under license from Vifor (International) Inc.,Switzerland.

(3.4%) in the two trials experienced severe adverse events that potentially were linked to the medication. However, in all cases “the underlying surgical or medical process or concomitant medications appeared to be more likely” to have been to blame, they said.

“What we see from the pharmacokinetic data is that the clearance of the drug is lower in newborns and children up to the age of 2, and then it achieves adult values after the age of 2,” Dr. Krane said. “So, there will have to be different dosage recommendations for newborns, for children from 1 month to 2 years of age and for children older than 2.”

The researchers identified a single case of transiently elevated liver enzymes.

Hepatotoxicity is “a big issue,” Dr. Krane said, but one that is misunderstood.

“Acetaminophen by itself is not hepatotoxic. There’s a metabolite that accumulates under abnormal circumstances which is hepatotoxic.”

The findings were presented at the 2009 annual spring meeting of the American Society of Regional Anesthesia and Pain Medicine (abstract 88).

—Staff

TOXICITY continued from page 29

were managing the medication of the patients in this study.

“My guess is that in many of these cases [of analgesic-related death], it is probably not someone who is familiar with the management of pain,” he said.

“Patients will be on double meds, maybe even triple, for months following the surgery, because they get used to a level of medication. Ideally, they can be weaned off in a few months, but again, we are probably talking about this being done by a surgeon or someone who has no experience with pain management.”

Dr. Juratli said the strong link between analgesic-related deaths and opioids was partially a byproduct of the fact that opioids were much more commonly used compared with nonopioids. “We provided some references of the recent upward trend of using more potent opioids and the more liberal dosing practices as a possible explanation of why opioid-related deaths were clustered after 2001,” she said. Dr. Juratli added that Washington state has opioid dosing guidelines “that speak to controlling opioid dosage.”

Dr. Kloth said that for many of these patients, less invasive interventional procedures, such as intradiscal electrothermic therapy may be simpler, less dangerous options.

—Donald M. Pizzi

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HYPONATREMIA DEATHS continued from page 1

“1,000 cc D5W–600 cc q8h,” according to ISMP’s report in its Aug. 13 newsletter. “An experienced pharmacist accidently calculated the infusion rate incorrectly and entered 200 mL per hour instead of 75 mL per hour on the child’s electronic medication administration record [MAR].”

A British physician who drafted and co-authored recent guidelines on the use of hypotonic saline solution for the UK National Patient Safety Agency said he was “appalled” that U.S. physicians are still permitted to prescribe plain D5W as a maintenance fluid to children in the postoperative period. The British guidelines, he noted, require that hospitals remove the most hypotonic saline solutions from general pediatric areas, and recommend that children in the perioperative period receive only IV fluids that pose no risk for causing hyponatremia.

“Even without the calculation error on the infusion rate, this child could still have developed symptomatic hyponatremia,” said Stephen Playfor, MD, a consultant pediatric intensivist at Royal Manchester Children’s Hospital in Manchester, England. “The death of this child would have been avoided if the doctor had ordered fluid such as 5% dextrose with 0.9% sodium chloride, even with the subsequent drug error.”

A clinical pharmacy specialist in pediatrics and pediatric surgery agreed that the use of plain D5W should be reconsidered in light of the new case report.

“D5W is generally floor stock, but in light of the ISMP report, perhaps it shouldn’t be,” said Katherine H. Chessman, PharmD, FCCP, BCPS, BCNSP, professor of clinical pharmacy and outcomes sciences at the Medical University of South Carolina, Charleston. “Only in the settings of hypernatremia or urine replacement in patients with diabetes insipidus would D5W be appropriate,” she added. “As a maintenance infusion solution, it should never be used. Anytime D5W is ordered as a maintenance infusion, it should be questioned by the nurse and the pharmacist.”

Noting that plain 1/2 or 1/4 normal saline ordered as maintenance IV fluids also are extremely hypotonic, she said, “protocols or guidelines should require justification for infusing these solutions in any patient.”

Flawed Math Equation Proves Deadly In the case involving the pharmacist who made a calculation error, ISMP reported, “he used a calculator and performed the calculation twice but had set up the mathematical problem incorrectly. Thinking in terms of how many 600 mL ‘doses’ would be needed, he

accidentally set up the calculation as follows: 600 mL (the volume to infuse over eight hours) divided by 3 (the number of 600 mL ‘doses’ he thought would be needed for 24 hours) and arrived at a 200 mL per hour infusion rate.”

The error was not caught by the attending nurse, who said she had come to rely on the accuracy of the pharmacists because they “never made mistakes.” When the child became lethargic and began experiencing jerking movements, rigid extremities and rolled-back eyes, the surgeon attributed it to a dystonic reaction from promethazine. When the seizure-like activity intensified, the nurses called the child’s surgeon multiple times, but no one recognized the significance of the symptoms or caught the infusion error until a consulting pediatrician was called in. By then it was too late, and the child subsequently died.

The previously healthy child had undergone a routine outpatient tonsillectomy and adenoidectomy.

Michael R. Cohen, RPh, MS, ScD, president of ISMP, said the pharmacist “was a good practitioner and had never been involved in a medication error” previous to this case. “All of us, at one time or another, can make a mistake. Tragically,

‘We have never once identified an organization or individual or even a location [of a medication error]. That has been a major factor in the success of our program. Reporters or reporting organizations trust that we won’t do that so they feel safe in giving us the details.”

—Michael R. Cohen, RPh, MS, ScD

in this case it proved to be fatal. But that is why we report these occurrences, so other hospitals and pharmacists can learn from the error and put precautions in place to prevent future occurrences.”

Signs of Trouble Missed In Second Case In the second case, ISMP reported, “the child underwent surgery for coarctation of the aorta, a condition that had been identified in this other-

A Medication Safety Officer’s Take

T

he recent hyponatremia deaths in two 6-year-old children illustrate that much work needs to be done to prevent future fatalities, according to a pharmacist who serves as a medication safety officer at a major northeastern hospital. The pharmacist, who is remaining anonymous because of legal concerns over two nonfatal cases of hyponatremia that occurred at the hospital, offered the following tips to prevent the disorder: Narrow your focus. The literature throws a wide—and not always helpful—net when it comes to potential triggers of hyponatremia, including certain medications (e.g., diuretics, heparin, opiates, desmopressin, proton pump inhibitors) and disease states (e.g., renal and liver impairment, hypothyroidism or cortisol deficiency). “At our institution, that would cover nearly 75% of our patients, so it’s not a useful way to zero in on at-risk patients,” the pharmacist said.

A better solution? To look for a sigificant “delta” or change in lab values that precedes hyponatremia, and to have a system for alerting the health care team when the change takes place. Such efforts should focus primarily on at-risk patients such as the very young, the elderly and the very sick. “Once a clinician is notified of a critical value, the team can intervene to restore normal fluid balance.”

Develop order sets. After experiencing the two cases of hyponatremia, the northeastern hospital developed detailed order sets that all of its clinicians must use when prescribing fluids to post-op patients. “We basically removed the plain D5W as a routine fluid option,” the pharmacist said. “Now, the order sets only contain D5W 1/2 normal saline, or D5W and normal saline, as the fluids of choice.”

Do a self-analysis. At hospitals with computerized prescriber order entry systems, such as the one in place at the northeastern hospital, “it was relatively easy” to data-mine the system and identify instances where fluid therapy was placing patients at risk for hyponatremia, the pharmacist said. “Every hospital really should do this.” Hospitals that don’t have e-prescribing in place shouldn’t balk: “You can look at this prospectively on paper; take a one-week snapshot, and you’ll see where the trouble spots are.”

Watch your speed. The medication safety officer agreed with the ISMP’s recent caution that “irreparable harm” can occur if the right pace isn’t followed when correcting low sodium levels. “Once we eliminate the source of the free water, we typically recommend increasing the sodium by 4 to 6 mEq over the first 1-2 hours, with an isotonic or near isotonic sodium chloride solution.”

—David Bronstein

wise asymptomatic, healthy child during a school physical.”

On postoperative day 1, the child’s physician prescribed a furosemide infusion (1 mg/h) because the child’s urinary output was lower than expected despite several doses of ethacrynic acid.

By postoperative day 2, ISMP reported, “the child’s serum sodium level had dropped, so his physician prescribed an infusion of sodium chloride. It is uncertain whether the sodium chloride was ever administered, as the child’s sodium level continued to drop and administration of the prescribed infusion was never documented on the MAR.” Despite ongoing, repeated concern expressed throughout postoperative day 2 by the parents about their inability to wake their son, nurses assured them that deep sleep was due to the pain medication, hydromorphone. As in the other case, nurses failed to recognize the symptoms of severe, lifethreatening hyponatremia, and the child subsequently died.

ISMP identified two common causes of the events: “lack of professional staff knowledge regarding the causes and signs of hyponatremia, and the failure of professional staff to respond to concerns expressed by several nurses in case 1, and by the parents in case 2, regarding the rapidly deteriorating condition of these children.”

Although reports of hyponatremia are hardly new, these new reports reinforce the need for a review by all health systems of their clinical management and best practices for postoperative pediatric care, said Christian A. Hartman, PharmD, MBA, assistant professor of medicine at the University of Massachusetts Department of Pharmacy and medication safety officer at UMass Memorial Medical Center in Worcester.

He identified six principles followed at

•

see HYPONATREMIA DEATHS, page 32

32 Clinical

Pharmacy Practice News • October 2009

Medication Safety

HYPONATREMIA DEATHS continued from page 31

her institution: 1. Protocols limit the use of dextrose, 1/4 normal saline and large volume administered via the parenteral route of administration. Additionally, IV preparation guidelines for pediatrics limit the use of large-volume, 1/4 normal saline and dextrose-containing products.

2. Standard order sets employ the use of preprinted order forms with specific, standard concentrations and diluents for dilution. Where possible, dextrose, 1/4 normal saline and large-volume infusion bags are eliminated.

3. Electronic clinical decision support surveillance aids practitioners in identifying high-risk patients and inappropriate fluid management. Real-time notification can be used to initiate clinical intervention.

4. Implementation of a rapid response team in pediatrics to better react to changing patient conditions. Clinical findings and laboratory results may be used to enact the rapid response team.

5. Conduct annual age-based competency for pharmacists, providing timely, pertinent education in the form of a competency assessment for all pharmacists. Topics include the detection and management of hyponatremia.

6. Materials management removes all dextrose infusion bags greater than 150 mL from the patient care units.

tutions or individuals involved.

There were no media reports of the incidents, and the institutions involved have not chosen to identify themselves, he noted.

“We have never once identified an organization or individual or even a location,” Dr. Cohen said. “That has been a major factor in the success of our pro-

‘Although reports of hyponatremia are hardly new, these new reports reinforce the need for a review by all health systems of their clinical management and best practices for postoperative pediatric care.’

—Christian A. Hartman, PharmD, MBA

gram. Reporters or reporting organizations trust that we won’t do that so they feel safe in giving us the details.”

Additional details can be found in the Aug. 13 issue of the ISMP Medica-

tion Safety Alert! Newsletter, at http:// www.ismp.org/Newsletters/acutecare/ articles/20090813.asp.

—Dan Hurley

The risks associated with cattle thrombin may stay with patients long after surgery

1

Patients with antibodies to cattle thrombin products should not be re-exposed due to the risk of developing postsurgical immune-mediated coagulopathy.2 In a recent clinical trial, 1 in 6 surgical patients with likely prior exposure to cattle thrombin had antibodies to cattle thrombin.3 Minimize these risks with RECOTHROM RECOTHROM, the only recombinant human thrombin, is 100% free of cattle plasma and as effective as cattle thrombin.4,5

A Record of Fatalities Anyone who is familiar with the literature on hyponatremia must have gotten a tragic sense of déjà vu when the ISMP report first hit. According to the Aug. 13 issue of the ISMP Medication Safety Alert! Newsletter that addressed the deaths (“Administration of hypotonic saline or parenteral fluids without saline is physiologically unsound and potentially dangerous for hospitalized children”), the mishaps have been well documented. The alert cited a 2003 analysis that found more than 50 reported cases of neurologic morbidity and mortality, including 26 deaths, during a 10-year period resulting from hospital-acquired hyponatremia in children who were receiving hypotonic saline parenteral fluids (Pediatrics 111:227-230).

More than half of these cases occurred in the postoperative setting in previously healthy children who underwent minor surgeries, the ISMP noted.

As for the new cases, Dr. Cohen said, the fact that they came to light was in no small part due to the anonymous nature of the group’s Medication Error Reporting Program, which does not disclose any identifying information about the insti-

In a phase 3 study of RECOTHROM compared to cattle thrombin, adverse events were reported with similar frequency in both treatment groups, and no reported adverse events were considered causally related to antibody formation in either group. Limited data (n=6) exist regarding re-exposure to RECOTHROM.

Rethink your thrombin

Indication: RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.

Important Safety Information: For topical use only—do not inject directly into the circulatory system. Potential risk of thrombosis if absorbed systemically. Do not use for the treatment of massive or brisk arterial bleeding or in patients with known

hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins.

No speci¾c adverse events have been established as adverse reactions causally related to RECOTHROM administration. In a clinical study comparing RECOTHROM to bovine thrombin, adverse events were reported with similar frequency in both treatment groups. The most common event was incision site complication. Limited data (n=6) are available on repeat exposure to RECOTHROM.

Clinical 33

Pharmacy Practice News • October 2009

Medication Safety

Is D5W Isotonic or Hypotonic? Lethal Confusion Persists

H

ow can D5W have an osmolality similar to plasma in an IV bag, but become lethally hypotonic when infused into the body? However technical the explanation, the resulting confusion has led to hundreds of needless deaths due to hyponatremia in previously healthy children following routine surgery, said Stephen Playfor, MD, a consultant pediatric intensivist at the Royal Manchester Children’s Hospital in Manchester, England.

“One of the root causes of the whole problem of iatrogenic hyponatremia is confusion regarding terminology,” said Dr. Playfor, who drafted guidelines for the United Kingdom requiring that hospitals remove IV fluids that pose a risk for hyponatremia from general pediatric areas.

“The issue of terminology, what we mean by tonicity, is of key importance,” he said. “There are worldwide misconceptions about this issue. In the UK, education has been one of the main thrusts in dealing with these needless deaths.”

Please see Brief Summary of full Prescribing Information on next page.

References: 1. Ness P, Creer M, Rodgers GM, et al; the Recognition, Evaluation and Treatment of Acquired Coagulopathy Consensus (RETACC) Panel. Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety. Patient Saf Surg. 2009;3(1):8. 2. Thrombin-JMI [package insert]. Bristol, TN: King Pharmaceuticals, Inc.; 2007. 3. Singla NK, Ballard JL, Moneta G, Randleman CD Jr, Renkens KL, Alexander WA. A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg.

2009;209(1):68-74. 4. Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the ef¾cacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.

5. RECOTHROM [package insert]. Seattle, WA: ZymoGenetics, Inc.; 2009.

RECOTHROM is a registered trademark of ZymoGenetics, Inc. ©2009 ZymoGenetics, Inc. All rights reserved. RT264-00, July 2009

Although 5% dextrose in water has an osmolality similar to that of plasma when sitting in a plastic bag, the dextrose is rapidly moved across cell membranes into the intracellular spaces when infused into the body. As a result, a solution that is as thick as blood in the bag becomes as thin as water in the human bloodstream—a problem worsened by the body’s release of antidiuretic hormones during illness, Dr. Playfor said. The salutary solution to this confusion over diluted solutions? Simply put, D5W and other potentially hypotonic solutions should be taken off the general pediatric floor, Dr. Playfor said.

“Ideally you’d want to use a solution with the same amount of sodium and chloride as found physiologically,” he said. “Hartman’s solution is the most physiologic solution around. It’s fine in the perioperative period, but it’s not for everybody. If you added 3% or 4% dextrose, it would be much more suitable for 98% of children’s fluid maintenance requirements.”

—Dan Hurley

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REFERENCES 1

Pharmacy Practice News • October 2009

Despite Claims, ‘Never Events’ Rules Generate Paltry Savings Study of California hospitals sees few financial gains from new CMS payment policies

T

wo years ago, the Centers for Medicare & Medicaid Services announced it would stop reimbursing hospitals for eight “reasonably preventable” hospitalacquired conditions and infections in order to improve patient care.

The agency predicted billions of dollars in cost savings from the move. But while the true impact from the new rule remains to be seen, a new study suggests that the projected savings may amount to only $1.1 million to $2.7 million annually, a pittance compared with Medicare’s $413 billion budget and not enough to encourage providers to improve quality of care.

The study, published in the September/October issue of Health Affairs (2009;28:1485-1493), analyzed patient discharge data for 2006 from the California Office of Statewide Health Planning and Development for six avoidable conditions (data for the other two conditions were commingled in broader categories). Of 767,995 acute inpatient Medicare discharges, hospital-acquired conditions were found in only 828 (0.11%) and only 26 (3.1%) of those would have been affected by the new CMS policy.

Reduced Medicare payments to California hospitals would have totaled between $92,000 and $227,000. Extrapolated nationwide, expected savings would have been no more than $2.7 million annually—a “negligible” amount that is “unlikely to encourage providers to improve quality,” concluded authors Peter D. McNair, MPH, and Andrew B. Bindman, MD, both at the University of California, San Francisco, and Harold S. Luft, PhD, director of Palo Alto Medical Foundation Research Institute.

Although the study was limited to California, which treats 8% of the nation’s Medicare acute inpatients, the distribution of hospital-acquired conditions was similar to that in other states, the researchers said.

CMS announced two years ago that it will no longer pay hospitals for eight infections and conditions that develop after admission, effective October 2008.

Those conditions include catheter-associated urinary tract infections; vascular catheter-associated infection; mediastinitis after coronary artery bypass graft surgery; decubitus ulcers; hospital-acquired injuries from falls and burns; and three serious preventable or “never events”— objects left in after surgery, air embolism and blood incompatibility.

This year, CMS added three more conditions: surgical site infections following certain elective surgeries, including orthopedic surgeries and bariatric surgery for obesity; extreme blood sugar derangement; and deep vein thrombosis/ pulmonary embolism.

The CMS rule applies only to Medicare Part A reimbursements to hospitals, not Part B payments to physicians. However, anesthesiologists expressed concern at the time that some proscribed infections and conditions will occur despite precautions and hospitals might seek to assign blame when that happens. Those worries have not abated.

“Patients will fall out of bed; infections will occur; patients may unexpectedly die in surgery or labor without any fault of the practitioners or the institutional system of care involved,” said Kenneth Y. Pauker, MD, an anesthesiologist in private practice at Saddleback Memorial Medical Center, in Laguna Hills, Calif., and chair of the legislative and practice affairs division of the California Society of Anesthesiologists.

“Just show us some evidence that penalizing folks in an all-or-none manner has some significant effect on the incidence of these events.”

In addition, hospitals are expending “tremendous amounts” of resources on staff and information technology to document that conditions were present on admission and therefore are not their fault, said Mark Singleton, MD, an anesthesiologist in private practice in San Jose, and adjunct clinical professor at Stanford University School of Medicine.

“How’s that resulting in cost savings, and to whom?”

In a perspective piece accompanying the California study (Health Aff 2009;28:1494-1497), CMS chief clinical officer Barry Straube, MD, and Jonathan D. Blum, director of the Center for Medicare Management, acknowledged that the projected payment reductions are not large. However, they argued, “small payment penalties have been effective in changing human behavior and ultimately in improving the hospital care experience for patients.”

The authors also noted that many state Medicaid programs and commercial insurers have adopted similar policies, and said that CMS will “refine these policies as appropriate.”

—Ted Agres

Q & A 35

Pharmacy Practice News • October 2009

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36 Operations & Management

Pharmacy Practice News • October 2009

Education

Pharmacy School Makes Mark on Industry An impressive record for oncology drug development

T

he School of Pharmacy at the University of Kansas, in Lawrence, has greatly influenced the pharmaceutical industry for more than four decades, helping to formulate a wide variety of drugs now on the market, including Gardasil (Merck & Co.), the vaccine used to prevent cervical cancer in young women.

Although the pharmacy program is relatively small and snugly nestled in

the conservative Midwest, it has for some time been a place of discovery and innovation. And research-focused schools like Kansas not only offer up new treatments to the industry, but they attract quality students, worldclass scientists and government funding, and benefit the local economy.

The school opened in a two-room basement in 1885 as the third state

(ClCH2CH2)2N———

university pharmacy in the nation. It has not always been oriented toward research and drug delivery, but when Professor Takeru Higuchi, known by many as the “father of physical chemistry” was lured to the campus in 1967, its direction changed dramatically.

Since then, the school has boasted impressive drug development numbers.

University of Kansas (KU) researchers

NH2 I —— —CH2 - - - C - - - COOH I H

have helped formulate seven of the last 19 cancer drugs from the developmental therapeutics branch of the National Cancer Institute (NCI). The school also consistently ranks in the top three pharmacy schools to receive funding from the National Institutes of Health.

“The school has a major strength in research and when pharmaceutical companies look at Kansas, that is what they

Operations & Management 37

Pharmacy Practice News • October 2009

Education think about,” said Kenneth L. Audus, PhD, dean of the School of Pharmacy.

“Research and education go hand in hand and education alone would become quite stale if we didn’t have research. In having top-quality researchers here, we are pushing the envelope in education.”

‘It really impresses students that these individuals who are teaching them are at the new frontiers of science and are bringing the latest in scientific discovery. It is cutting-edge and it makes a tremendous impression on students who are in the classroom.’

A Strong Cancer Pipeline Cancer drugs constitute almost half of the drug development pipeline at the school. This is mainly due to a contract the university has held with NCI for 30 years, in which KU helps the institute bring anticancer drugs through devel-

—Victor A. Yanchick, PhD opment and on to clinical trials. Pharmaceutical chemistry professor Valentino Stella, PhD, who has been with the school for 37 years, takes experimental

medications and works on formulation and delivery to get them through the pipeline and to patients.

The school’s newest accomplishment Valentino Stella, PhD, pharmaceutical chemistry professor at the School of Pharmacy at the University of Kansas, in Lawrence.

is Nanotax, a reformulation of the cancer drug paclitaxel, which helps fight ovarian, breast and other kinds of cancers.

Although the medication has been a success on the market, some patients suffer a serious allergic reaction to the solvent in which the drug is mixed. To avoid this problem and increase survival rates, KU researchers have broken the drug down into nanoparticle form so it can be mixed with water and then administered to patients.

Nanotax will be the first drug to move from bench to bedside at the university— it was formulated at the school, licensed through CritiTech Inc. (a university research and development spin-off firm) and is currently undergoing trials at the KU Cancer Center (KUCC) just outside of Kansas City, Mo. The ability to move a drug forward in this way is a huge boost to the pharmacy school, university and state, according to Victor A. Yanchick, PhD, immediate past president of the American Association of Colleges of Pharmacy and dean of the Virginia Commonwealth University School of Pharmacy, in Richmond.

“When you look at the costs incurred of bringing a drug to the market, a university can do it for a fraction of a percent of what it would cost a pharmaceutical company,” he said. “It is a cost-effective way to bring new entities to the market.”

Clinical Trials Close to Home The interaction between the pharmacy and the cancer center is creating an opportunity for patients to have the first opportunity to take part in clinical trials close to home, instead of traveling hundreds of miles to the likes of the University of Texas M.D. Anderson Cancer Center, in Houston. “In the Midwest, folks don’t have any place to go that is a major cancer center,” Dr. Audus said. “This is powerful to this region. This capacity will allow us to bring other substances along more quickly once we have established that trail and are successful with it.”

•

see PHARM SCHOOL, page 40

38 Operations & Management

Pharmacy Practice News • October 2009

Emergency Medicine Part 1 of a 2-Part Series

ED CARE continued from page 1

American Society of Health-System Pharmacists Foundation, each took a different tack to determine the impact of dedicated ED pharmacists on medication safety. One, a larger, multicenter study, used trained pharmacy residents to observe ED pharmacists’ interventions that prevented potentially harmful errors that had already occurred from reaching patients. The other study aimed to capture all medication use errors, from minor missteps of no consequence to

those with a potential for serious patient harm.

During the multicenter study, ED pharmacists at four academic medical centers reviewed 17,320 medications over a six-month period in 2008. They discovered 505 errors (an average of 7.8 errors per 100 patients and 29.2 errors per 1000 medications), thus preventing these errors from reaching patients. The most common medication classes involved in Abbie Erickson and Kristin Munz (pharmacists), errors were antimicrobials (32%), working with the surgical team in the Brigham and Women’s Hospital Emergency Department. central nervous system agents

Did you see the Special Report in last month’s Pharmacy Practice News?

For a free hard copy of this Special Report please visit pharmacypracticenews.com

Published By:

NEXT MONTH: New data from the ACCP on the value of ED pharmacy care (16%) and anticoagulants/thrombolytics (14%). Serious errors included underdosing (16.8%), overdosing (12.5%), drug omissions (10.5%) and wrong drugs (6.8%).

In one example of a wrong-drug error noted by researchers, an ED pharmacist’s recommendation that a physician change an order from succinylcholine to rocuronium for a severely hyperkalemic patient undergoing rapidsequence intubation avoided a potentially serious adverse drug event. In another case, an ED pharmacist caught and corrected a nurse’s transcribing error that could have led to a massive heparin overdose.

Lessons That Translate To Other Facilities This study demonstrated “the important role that emergency department pharmacists have in patient safety,” noted Jeffrey M. Rothschild, MD, MPH, an internist at Brigham and Women’s Hospital and patient safety expert. Dr. Rothschild, who led the multicenter study, which was conducted at Brigham and Women’s as well as Cedar-Sinai Medical Center, in Los Angeles, Grady Health System, in Atlanta, and the University of Wisconsin Hospital and Clinics, in Madison, said that the study offered lessons that could be “translated to other institutions” about the value of allowing pharmacists to be more proactive in uncovering drug errors in the ED. In the second study, a clinical pharmacist/researcher shadowed different ED nurses for 12-hour shifts over nine months at the University of Arizona Medical Center, in Tucson. All aspects of the medication use process, including medication errors, were recorded.

Asad Patanwala, PharmD, BCPS, clinical assistant professor of critical care/ emergency medicine at the University of Arizona College of Pharmacy, in Tucson, identified a total of 178 medication errors in 192 patients—or one error for every five doses ordered—as he followed approximately 18 different nurses. The nurses quickly became accustomed to his presence, he said, avoiding the socalled Hawthorne effect in which the presence of an observer changes the behavior of the person being studied.

Dr. Patanwala found that nearly six out of 10 patients (59.4%) had one or more errors. Most errors were relatively minor.

Almost four out of 10 patients (37%) had errors that reached the patient but did not cause harm—category C in the severity rating scale devised by the National Coordinating Council for Medication Error Reporting and Prevention. One category E error led to temporary harm and

Operations & Management 39

Pharmacy Practice News • October 2009

Emergency Medicine

The ED pharmacy team at the University of Arizona College of Pharmacy, in Tucson (left to right): Daniel Hays, PharmD, Asad (Sid) Patanwala, PharmD, and Arthur Sanders, MD.

required intervention. Under the study protocol, Dr. Patanwala could intervene when he observed an error having the potential for patient harm. During his observations, there were no errors more serious than category E. (In the worstcase scenario, a category I medication error results in a patient’s death.)

The study also looked at the point in the medication use process at which the errors occurred. It found that administration accounted for 34.8% of the total, prescribing 53.9%, transcribing 10.7% and dispensing 0.6%. Variables that were predictive of medication errors were the quantity of medication orders (odds ratio [OR], 1.25; P<0.001); boarded patient status (OR, 2.15; P=0.043); and presence of part-time versus full-time nurses (OR, 0.37; P=0.021). Other variables were not significant, including patient age and sex, years of nursing experience and day versus night shifts.

The study was conducted before the medical center’s ED expanded from 40 to 80 beds and acquired the services of a full-time emergency pharmacist. Now, Dr. Patanwala said, the emergency pharmacist provides 40 hours of coverage and he works another 10 for a total of 50 daytime and evening hours each week.

The study was also done before the recent implementation of a computerized physician order entry (CPOE) system in the ED. Although Dr. Patanwala has no scientific evidence showing that the changes have improved ED medication error rates, he suspects that it might be the case, particularly because the CPOE system now requires the input of information that might have gone unspecified before, such as the route of administration for a morphine order. It also flags orders lacking a patient’s drug allergies. “That was one of the trends we saw—people given medications they were allergic to,” Dr. Patanwala said.

More Kudos for Research Efforts Dr. Acquisto, of the University of Rochester, said the results of these studies validate the growing importance of

having a specially trained clinical pharmacist involved in emergency care. And they underscore how well-positioned the profession is to provide that care.

“This environment poses unique medication safety challenges due to a multitude of factors including high patient volume, incomplete medical records, and frequent use of verbal and handwritten orders,” she said. “The emergency pharmacist is uniquely poised to improve medication safety and has therefore gained the support of ED leadership at institutions across the country.”

Daniel P. Hays, PharmD, BCPS, clini-

cal pharmacist in the Department of Pharmacy and of Emergency Medicine at University Medical Center– University of Arizona, in Tucson, had been part of a team that won an ASHP Best Practices Award in 2005 for a study that showed pharmacists enhanced patient safety during trauma resuscitations. Dr. Hays and his former colleagues from the University of Rochester found that an emergency pharmacist improved “patient care by reducing errors and providing another layer of patient safety during a critical resuscitation period.”

Dr. Hays noted that “from a sheer numbers perspective,” the odds are great for a medication error to occur when many of the hundreds of doses dispensed daily from an automated dispensing machine are administered without a pharmacist’s intervention. However, he added, “when an emergency pharmacist is present, we’re not only able to review those orders but also to provide correct feedback to physicians when they’re writing the orders and, in turn, to minimize any potential for medication error.”

—Bruce Buckley

40

Hem/Onc Pharmacy

Pharmacy Practice News • October 2009

In Focus

TKIs continued from page 14

mutation, a criterion for suitability. The new data from Dr. Paz-Ares, if confirmed, will have a similar implication. For clinicians, this means that tissue biopsies or another form of tissue sampling must be incorporated into routine patient care.

“I believe we are now rapidly moving to a primarily molecular-based therapy from a primarily empiric-based therapy in lung cancer,” said David R. Gandara, MD, director of the Thoracic Oncology Program at the University of California, Davis Cancer Center, in Sacramento, Calif. Echoing an often-repeated theme regarding the coming importance of tissue sampling and molecular profiling in routine care, Dr. Gandara, who was a cochair of the World Conference on Lung Cancer, indicated that the shift is already under way.

For many, it has already taken place.

Philip Bonomi, MD, director of the Divi-

sion of Hematology and Oncology, Rush University Medical Center, in Chicago, said that he is already ordering EGFR mutational profiles in all nonsmokers before initiating therapy. In those patients who do have the mutations, clinicians administer a TKI first-line.

Although studies have shown that this treatment decision may only improve PFS, he considers this a “reasonable” approach based on current science.

It is estimated that mutations in the tyrosine kinase domain of EGFR occur in 10% of whites and up to 30% of Asian patients with advanced NSCLC. The mutations are most common in female nonsmokers, but clinical characteristics provide poor sensitivity and specificity for the presence or absence of the mutations. Although level 1 evidence does not yet support the use of routine biopsies of advanced NSCLC to test for EGFR mutations, there is a growing conviction among clinicians that these data are forthcoming.

At M.D. Anderson, Hem/Onc Pharmacists Support EGFR Testing Makala B Pace, PharmD, BCOP, clinical pharmacy specialist, thoracic, head and neck cancers at The University of Texas M.D. Anderson Cancer Center, in Houston, said that her institution has also embraced EGFR mutation testing.

“We’re doing the tests pretty much in all of our patients who have non smallcell lung cancer,” she said. “It’s been in been in place for about two to three months,” and was spurred, at least in part, by the recent trial data showing the test’s ability to accurately predict patient response to TKIs. But there are some caveats to genetic testing, Dr. Pace noted. For example, “a lot of the time we don’t have enough tumor tissue to actually do mutation testing on. So in those cases, we have to decide, is it important enough for us to know mutation status now, and if so, do we put the patient through a second

biopsy to get more tissue? Or is it something we could do without and treat empirically?”

In some cases, she said, the decision to go with TKI therapy can be based on documented predictors of response to the drugs. “If the patients are Asian, female, never smokers, or the initial tissue diagnosis shows that they have adenocarcinoma, those are good predictors of a robust response to TKIs, and so the physicians here are now leaning more towards using a TKI up front,” Dr. Pace said.

Depending on the performance status of the patient, “our physicians may decide to use the TKI in combination with a platinum doublet, as opposed to using it alone,” she added.

As far as which TKI to use, the only practical option is erlotinib; given the limits the FDA placed on gefitinib’s use in 2005, “the drug is essentially unavailable for use in the U.S.,” she said.

—Ted Bosworth

CLINICAL

Pain Medicine

PAIN EXPERTS continued from page 26

of prescribers, which is sort of a metaphor for modern-day pain management.

There are 460,000 unique prescribers of OxyContin (Purdue Pharma). It’s safe to say that 50,000 of those drive 80% of prescriptions. In the big urban centers, you will see no impact, but I would estimate that 200,000 of the remaining 400,000 will not seek certification. It will become increasingly hard to find someone who does state-of-the-art pain man-

agement. It will be even harder to get an appointment with such an expert.

Regarding certification of pharmacies, pharmacies in poor neighborhoods already don’t want to stock these medications. So, all they will have to do to justify this is to not seek certification and they are off the hook. It will become increasingly tough to be a pain patient, and it’s going to become especially difficult being a poor pain patient.

Dr. Lipman: I also wonder what effect certification of prescribers and pharma-

cies will have. That regulation will be a tough one to push through; there will be plenty of resistance in both the pain medicine and pharmacy communities. The net effect would be less use of opioids, including by patients who need them.

Certification also raises a related issue: Which physicians and caregivers are best suited to manage patients with chronic pain? In the case of primary care physicians, they have to know so much about so many things that they may not [be suited] to handle the challenge of treating chronic pain patients. It’s

not a criticism, it’s just an observation of what primary care is. A tongue-incheek description says that in primary care, clinicians learn less and less about more and more until they know nothing about everything. In specialty care, we learn more and more about less and less until we know everything about nothing.

It may seem a bit flippant, but there is truth to both of those aphorisms.

—Compiled by Adam Marcus, Donald M. Pizzi and David Bronstein

OPERATIONS & MANAGEMENT

Education

PHARM SCHOOL continued from page 37

The Nanotax trial also is playing a large role in the KUCC’s bid for NCI designation as a major cancer center with the capacity for drug development, said Erica Brown, spokeswoman for the KUCC. “One of our goals is to be the No. 1 cancer center producing cancer-fighting drugs,” she said.

Dr. Stella, co-creator of Nanotax, said the pharmacy program offers something distinctive to KU’s proposal for NCI designation. “One of the things that is unique about the program is most other cancer centers are associated with medical centers, but don’t have a drug discovery and delivery component,” he said.

The school also has helped grow the local economy. A new site is currently being built from funds raised by the

program. Across the street from the new pharmacy school administration office will be research incubator space for companies (like CritiTech) that come from the university.

“This space will be where technologies, drugs and products that spin out of KU will have inexpensive space to start up and hopefully grow the economic base,” Dr. Stella said.

Although the school has formulated various high-profile cancer medications, the researchers also work in other areas including neuroscience, neurodegenerative diseases and infectious diseases. Out of Dr. Stella’s lab came the anticonvulsant medication fosphenytoin sodium injection (Cerebyx, Pfizer) and a drug used in anesthesia care, fospropofol disodium (Lusedra, Esai Corp.).

As far as Dr. Stella is concerned, it doesn’t really matter what area the

research is in, as long as the school is taking part.

“Different people have different philosophies on things like that, but I think it’s dangerous for a school of pharmacy not to have a research component,” he said.

“Students will parrot what was learned by others. If schools only use information generated by others, then who is going to generate the information?”

Pharmacy programs that have research capabilities also offer a richer experience for the students, he said. Dr. Stella offers anecdotes from his own lab and research to accompany material in the textbooks. He also is in demand from the pharmaceutical industry and as an expert witness in patent litigation—only adding to the aspects he can bring into the classroom.

“It really impresses students that these individuals who are teaching them are

at the new frontiers of science and are bringing the latest in scientific discovery,” Dr. Yanchick said. “It is cutting edge and it makes a tremendous impression on students who are in the classroom.”

Perhaps the most important benefit of having extensive research capabilities is being able to provide that experience for students, some of whom may choose drug development as a career.

Students planning to work as pharmacists and those planning to go into the industry and create new medications to cure diseases are attracted to these kinds of schools.

“What we hope to do is impart the same knowledge to them [students],” Dr. Stella said. “We are trying to grow the next generation of scientists when the old fogies have one step out the door.”

—Tammy Worth

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Barbara B. Hodgson; Robert J. Kizior

Written by a unique nurse/pharmacist author team, Saunders Nursing Drug Handbook presents drug information in an order that reflects your thought process when a prescription is ordered. It helps you provide better patient care by guiding you through clinical priorities in the practice setting and with comprehensive coverage of I.V. drug administration. Organized alphabetically by generic drug name, this handbook is an easy-to-use guide to thousands of medications. It’s ideal for the busy nurse!

Stephanie J. Phelps; Emily B. Hak; Catherine M. Crill

Teddy Bear Book, Pediatric Injectable Drugs, the only reference that compiles I.V. and IM administration recommendations specifically for pediatric patients, has been updated.

Merck

The Merck Index Version 13.4 CD-ROM (Academic) is a single electronic reference of chemicals, drugs and biologically active molecules that includes more than 10,250 original monographs from the 13th edition, 540 monographs from the printed 12th edition and 230 new monographs from the upcoming 14th edition.

PPN1009

42 Technology

Pharmacy Practice News • October 2009

Automation

R U Robot Ready?

C

oncerns about the safety of patients undergoing chemotherapy, as well as technicians and nurses who are exposed to the toxic medications during preparation and delivery, have led several health-system pharmacy leaders to equip their IV rooms with chemotherapy robots.

At least one of these innovators said the technology has significantly reduced IV drug errors at his facility and given him peace of mind in the process.

“What goes on in the IV room during the day is what keeps many pharmacy directors awake at night,” said Bill Churchill, MS, RPh, executive director of pharmacy services at Brigham and Women’s Hospital (BWH), in Boston, which recently installed Devon Robotics’ CytoCare chemotherapy system.

“We have pharmacy technicians creating highly toxic, very dangerous IV admixtures that could harm patients, if done incorrectly.”

Why pursue a more automated approach to IV drug preparation? “Pharmacists can’t stand over a nurse or a technician’s shoulder every minute and verify that every single step in the preparation process is done correctly,” he said.

BWH has taken several steps to improve the IV admixture process.

One of the first was to implement bar code verification in their sterile product suite. “The bar codes ensured we had the right drugs, but I sought automation to become even more safe, more accurate and hopefully maintain a good level of efficiency,” said Mr. Churchill, whose ultimate goal is to eliminate the preparation of sterile IV admixtures by human hands by using IV robotic technology. To that end, he is also bringing in an IntelliFill robot (ForHealth Technologies, Inc.) and will serve as a beta site for Health Robotics’ IV Station robot. BWH could have as many as five robots on-site when the strategic plan is finished, he added.

BWH: $1 Million Annual Savings Bringing IV Prep In-house The hospital’s robotic strategic plan is predicted to save a net $1 million per year by pulling away business from IV compounding outsource companies.

“We’ve been preparing about 600,000 IVs annually and outsourcing a similar number,” noted Mr. Churchill. “We’ll eliminate the use of the IV outsource compounding companies and replace that with in-house IV robotic preparation. We expect to produce about 1 million IV admixtures annually in-house, including chemotherapy, prefilled syringes, IV bags, minibags, infusion and large-volume parenterals.” His

day-to-day operations, database issues and more.

BWH, which began testing the CytoCare robot in April 2009, and went live in June, became one of the first hospitals in the United States to have an operating HL7 interface between the robot and its self-developed pharmacy information system.

UCH To Consolidate Inpatient And Outpatient Chemo Prep With Robot

The University of Colorado Hospital, in Denver, continues to employ Devon Robotics’ CytoCare chemotherapy system to protect patients and health care workers against exposure to potentially harmful cytotoxic agents.

‘Pharmacists can’t stand over a nurse or a technician’s shoulder every minute and verify that every single step in the preparation process is done correctly.’

—Bill Churchill, MS, RPh estimate includes 60 to 80 inpatient doses of chemotherapy per day.

The CytoCare robot will fill the vast majority of the 60 to 80 doses each day—except for treatment protocols that require a manual “mix together” of three or more drugs. BWH is also already using the robot to make individualized doses of gentamicin and acyclovir, and might use it for monoclonal antibodies such as

infliximab (Remicade, Centocor Ortho Biotech) as well, noted Mr. Churchill.

The monetary savings projected by Mr. Churchill allowed him to create three new staff positions. Two are robotic technology coordinators, who will oversee the four or five other robotic technicians on staff. They will report to a new manager of pharmacy automation and technology, who is responsible for

Tips for Successful Robotics

H

ere are some lessons learned from centers that have recently installed chemotherapy robots:

• Dedicate a team to follow through on the many steps it takes to make the robot operational. Set it up, calibrate to the highest degree of accuracy, establish the database and add new drugs to it, run repeated tests of accuracy and efficiency and train staff.

• Be vigilant. Avoid the mindset that technology is infallible.

• Test each vial size at least 50 times through the robot to ensure that bugs are worked out. (Hospitals work with several dozen vial sizes.)

• Consider doing more IV preparation in-house in order to save compounding outsource fees and help fund the robotic investment.

• Have the technology vendor train super-users at your facility, who in turn can continue to train additional technicians.

• Create formulary maps from your top two vendors for particular drugs, so you can proceed with an alternate in case one suddenly goes into shortage.

This will minimize variance issues with respect to product concentration ad packaging.

• Consider a quality assessment program to ensure that robots function as they are designed to do.

Sources: University of Colorado Hospital, Brigham and Women’s Hospital.

The University of Colorado Hospital (UCH) is also live with the CytoCare unit, after having done a pilot rollout in 2007. But unlike BWH, the Denver hospital hasn’t established an interface with its pharmacy management system.

The UCH rollout of the CytoCare robot continues at a deliberate pace, with a target of progressing from 20 inpatient chemotherapy doses daily to an anticipated 50 daily in the next six months, once the hospital begins producing IV admixtures for the outpatient chemotherapy center on the same campus. That expansion is possible because ICU Medical partnered with CytoCare distributor Health Robotics to develop a closed-system bag spike that the robot can accept, according to Nancy Stolpman, PharmD, PhD, director of pharmacy at UCH. Since UCH implemented the robot, it has made zero errors. Dr. Stolpman recounted “occasional leaks in the robot chamber, predominantly due to our high altitude, which pressurizes the vials. Health Robotics taught the robot through the manufacturer’s software how to adapt. The hospitals in Europe that have longer histories using the robot are at sea level.”

Of 23 pharmacy technicians who work shifts in the IV room at UCH, six work the robot, having been trained primarily by one super-user. “The robot won’t let you load the wrong drug or put it in the wrong place. The right touch is necessary, however. If a technician places a needle too tightly on a syringe, the robot might not be able to remove it; if too loose, the needle could fall off,” she noted.

Drug Manufacturer Variance A Key Concern One of Dr. Stolpman’s biggest operations issues is the variance between manufacturers in the packaging (syringes, bags, vials) of drugs such as cisplatin.

“We acquired this medication regularly from one manufacturer, whose neck size and vial depth worked with the robotic arm. During a national shortage of the drug, we found another supplier whose

•

see ROBOTICS, page 45

BRIEF SUMMARY: For full prescribing information, see package insert.

VOLUVEN

®

Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches.

For administration by intravenous infusion.

Initial U.S. Approval: 2007

Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]

To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@ hospira.com or FDA at 1-800-FDA-1088 or electronically at www.fda.gov/medwatch.

6.2 Adverse Reactions in Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice.

(6% HYDROXYETHYL STARCH 130/0.4 IN 0.9% SODIUM

CHLORIDE INJECTION)

1

INDICATIONS AND USAGE

Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells or coagulation factors in plasma.

4

CONTRAINDICATIONS

The use of Voluven® is contraindicated in the following conditions: •

known hypersensitivity to hydroxyethyl starch [see General Warnings and Precautions (5.1)]

•

fluid overload (hyperhydration) and especially in cases of pulmonary edema and congestive heart failure

•

renal failure with oliguria or anuria not related to hypovolemia

•

patients receiving dialysis treatment

•

severe hypernatremia or severe hyperchloremia

•

intracranial bleeding.

5

WARNINGS AND PRECAUTIONS

5.1 General Warnings and Precautions Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. [see Adverse Reactions (6)] Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction.

In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration.

Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease).

5.2 Monitoring: Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation.

5.3 Interference with Laboratory Tests Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis.

At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit.

6

ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows:

Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)]

Voluven®,

During clinical development, 471 patients were exposed to and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days.

In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.

Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group.

6.3 Postmarketing Experience The following adverse reactions have been identified during the postapproval use of Voluven® and other types of hydroxyethyl starch solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8.4 Pediatric Use In one trial, children including newborns to infants (<2 years) undergoing elective surgery were randomized to receive Voluven® (N=41) or 5% albumin (N=41). The mean dose of Voluven® administered was 16 ± 9 mL/kg3).

Voluven® may be given to premature infants and newborns only after a careful risk/benefit evaluation. The safety and efficacy of Voluven® have not been established in the age group of 2 to 12 years. Use of Voluven® in children >12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults and by data from children <2 years old. Dosage in children should be adapted to individual patient colloid needs, taking into account underlying disease, hemodynamics and hydration status. [see Pediatric Dose (2.2)] 8.5 Geriatric Use Of the total number of subjects in clinical studies of Voluven® (N= 471), 32% were 65 years old and older while 7% were 75 and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal impairment Voluven® is mainly excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Volume status, infusion rate, and urine output should be closely monitored. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. [see Pharmacokinetics (12.3)] 10 OVERDOSAGE As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)] 15 REFERENCES 1)

Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive large-dose infusion of the novel hydroxyethyl starch HES 130/0.4 in patients with severe head injury. Anest Analg 2003; 96 (5): 1453–9

2)

Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005; 103 (3): 654-60

The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product.

3)

Lochbühler H, Galli C, Hagemann H. Hydroxyethyl starch HES 130/0.4 in paediatric surgery: results of an explorative, controlled, multicenter safety study. Crit Care 2003; 7 (Suppl 1):, P107

Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®.

4)

Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch.

Clin Pharmacokinetik 2005; 44 (7): 681-699

5)

Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 2002; 95 (3): 544 – 51

6)

Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F. Tissue storage of 14C-labeled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4 (6): 331-8

7)

Gandhi SD, Weiskopf RB, Jungheinrich C et al. Volume replacement therapy during major orthopedic surgery using Voluven® (hydroxyethyl starch 130/0.4) or hetastarch.

Anesthesiology 2007; 106:1120-1127

With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2).

8

USE IN SPECIAL POPULATIONS

8.1 Pregnancy Pregnancy Category C. Voluven® has been shown to cause embryocidal or other adverse effects in rats and rabbits when given in doses 1.7 times the human dose. There are no adequate and wellcontrolled studies in pregnant women. Voluven® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The type of hydroxyethyl starch present in Voluven® had no teratogenic properties in rats or rabbits. At 5 g/kg of body weight per day, administered as a bolus injection, fetal retardations and embryolethal effects were observed in rats and rabbits, respectively.

In rats, a bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays.

All adverse effects were seen exclusively at maternal toxic doses due to fluid overload. [see Toxicology (13.2.1)] Fertility studies on directly exposed animals have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes: Polyolefin bag (freeflex®) with overwrap: 500 mL Carton of 15 x 500 mL NDC 0409-1029-01 Store at 15° to 25°C (59° to 77°F). Do not freeze.

8.2 Labor and Delivery Information on the use of Voluven® during labor or delivery is unknown.

Manufactured by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Voluven® is administered to a nursing woman.

Distributed by: Hospira, Inc. 275 North Field Drive Lake Forest, Illinois 60045 USA Made in Norway Reference EN-1597

Technology 45

Pharmacy Practice News • October 2009

Automation

ROBOTICS continued from page 42

vials were different enough that the robot couldn’t work with it. The original supplier eventually released the drug, but now in a vial outside of robot parameters. We ended up finding a product that worked, but it took a while to figure it out,” she said. To eliminate that incompatibility, BWH’s Mr. Churchill urged hospitals to “create formulary maps from your top two vendors for particular drugs, just in case.”

Another aspect of variance—one of great concern to both Mr. Churchill and Dr. Stolpman—is the variance in actual product concentration versus labeled concentration. “The United States Pharmacopeia requires that all compounded products be within a range of ±10% of labeled concentration. This can lead to some degree of variability in the actual concentration of the final product,” he said. Currently, both BWH and UCH have set a much lower tolerance limit of ±5% for the final product to pass, but even this raises questions for them.

“Do you fail a final preparation that comes in at 6%, and eat the $1,000 to $3,000 in drug costs?” posed Dr. Stolpman.

“What if a medication order is written for 1,000 mg and the bag is 980 mg (2% variance); do we let it go to the patient care area as is labeled at 1,000 mg, or do we label it with the actual amount of 980 mg and force a new order?” said Mr. Churchill, who is studying the effects of the CytoCare robot on safety, accuracy and worker exposure with medication safety gurus David Bates, MD, and Jeffrey Rothschild, MD, both also at BWH.

order for dispensing. Several steps were accounted for in the calculations, including pharmacist checks, data entry, final verification and bagging, etc.

The investigators found that the CytoCare robot required a median time of 33 minutes to fully complete a chemotherapy order for dispensing, compared with 34 minutes for a pharmacist/pharmacy technician.

Dr. Stolpman said the close time gap was due, in part, to wait times for a pharmacist to check the work of the robot.

“Future time studies may reveal improvements in robot efficiency,” she noted.

It’s also important to remember that there are key benefits beyond drug preparation time, Dr. Stolpman said.

“The robot does reduce the amount of cytotoxic drug exposures for patients, pharmacists and pharmacy technicians, and that was a major goal of implementing this technology.”

Dr. Stolpman acknowledged that her study did not compare the degree of such exposures in robot- versus humanprepared drug orders. “The statement [about reduced contamination] is based on the fact that the opportunity for exposure is significantly decreased, sim-

ply by how [the robot] works. For example, employees are no longer exposed to uncapped contaminated needles, eliminating the possibility of a needle-stick.”

As far as any more parsing of the poster study, Dr. Stolpman said, “I don’t think it called out the number one reason for doing this: patient safety (establishing best practices), followed by employee safety, and then efficiency.”

Based on the UHC’s experience with the robot to date, “we’re right on track with each of those key outcomes.”

—Al Heller

Comprehensive Quality Assessments on Tap “We’re developing a dynamic quality assessment program to make sure our robots are working as designed,” Mr. Churchill said. “We’ll use a combination of the CDEX ValiMed Medication Safety System, and an independent specificgravity weighing process that we have developed in-house for this purpose. We believe that this will be an effective way to monitor the robotic processes, and to help improve the processes and design new ones.”

In both approaches, he explained, the specific gravity of a prepared IV admixture is tested to ensure that it matches a reference value.

Dr. Stolpman and colleagues at UCH presented a poster study at the recent Hematology/Oncology Pharmacy Association meeting in Miami, documenting the efficiency of the CytoCare robot.

The study used time studies to calculate how long it took the robot versus a pharmacist/pharmacist technician to fully complete a chemotherapy drug

Coming soon from Cadence Pharmaceuticals—

IV acetaminophen © 2009 Cadence Pharmaceuticals, Inc

9/09

CAD1001

Printed in USA

www.cadencepharm.com

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0YVPX 52?2

Technology

In Brief SIUE School of Pharmacy Launches Site For Pain, Palliative Care Pharmacy

T

he Southern Illinois University Edwardsville School of Pharmacy has launched a new Web site, www. pharmacypainsummit.com, designed to encourage thought-sharing and learning among practitioners in pain and palliative care pharmacy.

The site is structured as a blog with comment sections to facilitate ongoing discussion among those involved with and interested in health care, pain management, palliative care and related pharmacy topics, the school noted in a press release.

The site was launched to coincide with the Strategic Planning Summit for the Advancement of Pain and Palliative Care Pharmacy, which was held on Thursday and Friday, Oct. 1-2, at SIUE’s School of Pharmacy.

Coordinator Chris Herndon, PharmD, assistant professor of pharmacy at SIUE, said the site will foster education and discussion about the concepts of pain and palliative care education and how those concepts pertain to today’s professional pharmacist.

“We’re encouraging online collaboration among pharmacists and have created the site as an open, collaborative space used to foster discussion among all health care providers,” Dr. Herndon said.

“We believe hosting this space is an added benefit not only for our students, but for the entire health care community.”

Dr. Herndon said recommendations that come out of the upcoming summit will lead to pharmacists putting what they have learned into practice. “I am urging health care practitioners and pharmacists to be as active as possible in disseminating recommendations by taking part in online discussion to be shared among colleagues.”

This year’s pain summit builds on the National Pain and Palliative Care Summit held in 2003 at The Ohio State University, Dr. Herndon noted. “It was then that a group of pharmacists with interest and/or expertise in pain and palliative care recommended that the next steps to effective change would be a profession-specific summit in which we, as pharmacists, could identify either the current short-comings in training and assessment, or focus on areas of success which could be mirrored.”

One clinical insight is greater than a mountain of data.

Today, caregivers need more than piles of data. They need insights that lead to better care. CareFusion is a new medical technologies company with 15,000 employees in 20 countries and one powerful mission: to fuse its proven technologies with actionable intelligence to provide insights that help improve patient care. To learn more, visit our website at carefusion.com.

—PPN Staff

Next month: details on the recommendations and debate coming out of the Strategic Planning Summit.

Alaris®

ChloraPrep®

Pyxis®

Viasys®

V. Mueller®

© 2009 CareFusion Corporation or one of its affiliates. All rights reserved. Alaris, ChloraPrep, Pyxis, Viasys and V. Mueller are registered trademarks of CareFusion Corporation or one of its affiliates. MC0803

48 Technology

Pharmacy Practice News • October 2009

Robotics

Getting Up to Speed on Carousel Implementation Introduction Numerous articles have been published on the error-reduction potential and operational efficiency gains of central pharmacy automation.1,2 Recognition of the potential safety gains has led to increased adoption of central pharmacy automation over the past decade, with at least one source reporting current usage at 10.2% of hospitals surveyed. This is up from 7.8% reported in 2002, and more than double the 1999 rate of 4.5%.3 One of the more contemporary entrants into this market segment is the automated pharmacy carousel system (APCS). The APCS is a 21st-century rendition of carousel-based medication storage that dates back to the 1970s. Unlike carousels from that era, however, modern APCS installations are partially or fully integrated with other pharmacy technologies (unitbased automated dispensing machines [ADMs], pharmacy information systems, wholesaler Web sites, etc).

The purpose of this article is to describe the installation, setup and use of an APCS in a 400-bed community hospital. Although my experience is limited to only one APCS vendor, the information presented should be applicable to any APCS.

Brian Peters, PharmD, MS Director of Pharmacy Community Hospital North Indianapolis, IN

to consider when choosing a location for an APCS include proximity to the medication receiving area, as well as to the entrance/egress doors used by technicians. Secondary considerations include accessibility of the carousels for service, integration with medication storage areas other than the carousel (controlled substance cabinets, refrigerated storage, etc), and availability of sufficient counter space for receiving/ dispensing activities. As some carousel pieces are quite large, vendors also will conduct an assessment of the physical space to ensure the presence of a navigable route from the loading dock to the pharmacy, adequate load-carrying capacity of the floor structure and sufficient overhead clearance.

not recognized by the software.

Products generally are received into the APCS in manufacturer packs (i.e., cartons of 25), but most commonly are removed as individual doses. To facilitate this workflow, the hospital took the additional step of scanning not only the outer packaging of products, but also the bar code on each individual dose pack.

This extra step also provided the hospital with a very robust bar-code database for use in subsequent implementation of bar-code medication charting.

Balancing Multiple Carousels Many institutions will find it necessary to install multiple carousels (CHN decided on two 12-foot units). When multiple carousels are used, the most efficient plan is to equally divide the most commonly dispensed medications between the carousels. To accomplish this task, CHN obtained a dispensing report from its pharmacy information system and ranked the data in descending order of use. The 200 most frequently used medications were then equally divided between the two carousels (the most

Hospital Background Community Health Network is a fivehospital system located in Indianapolis.

With nearly 1,000 total beds, Community Health Network is the largest nonacademic hospital system in the metropolitan Indianapolis area. Community Hospital North (CHN) is the largest hospital in the system, with more than 400 beds providing medical, surgical, intensive/ progressive care, maternity, neonatal, pediatric and behavioral care treatment to residents of the northeastern portion of metropolitan Indianapolis.

In late 2006, vendor selection for central pharmacy automation at CHN was completed when Talyst was selected.

The implementation process began in early 2007. Although the implementation consisted of numerous components (carousels, software, automated packaging system, bar-code labelers), this article focuses specifically on implementation of the APCS.

Pharmacy Layout CHN had the distinct advantage of installing the APCS in conjunction with a complete redesign and expansion of the existing inpatient pharmacy space, thus allowing for strategic placement of the carousels within the pharmacy to facilitate optimal product flow and staff efficiency. Key factors

The automated pharmacy carousel system in place at Community Hospital North.

Bar-Code Association One of the most important tasks, and one of the first that must be completed during initial carousel setup, is association of medications and their corresponding bar codes. This association serves as the foundation for the entire system and must be completed in a timely and accurate manner. Because of the potential risk and liability involved, CHN delegated this responsibility to a small number of specially trained pharmacists. These pharmacists were selected for training based on their extensive knowledge of the hospital’s formulary, which helped to ensure the efficiency and accuracy of the process.

During bar-code association, every attempt should be made to identify and scan bar codes on all in-stock generic products. This will help to ensure the implementation proceeds smoothly by reducing the number of medications

frequently used medications went into carousel 1, the next into carousel 2, etc.).

When performing this balancing process, be sure to exclude any controlled substances that will not be stored in the carousels. (See below for more information on considerations for storage of controlled substances.) Also be sure to take into account any storage areas that may be operated in conjunction with a carousel location, as this could influence the medications included in your velocity assessment.

Medication Location Within Carousels In addition to the frequency of use, there are a number of other factors that should be considered when determining the physical location of medications within the APCS. One of the biggest advantages of carousel storage is the ability to dispense with alpha-

betical storage of medications. Much has been published regarding the potential for medication error when products with similar names (either in spelling or pronunciation) are located in close proximity.4-6 Thus, staff assigned to load the carousels should have a copy of the facility’s “look-alike/ sound-alike” (LASA) medication list and should reference it throughout the loading process. In addition to physically separating medications on the LASA list, every effort also should be made to segregate different strengths of the same product.

Another consideration when loading inventory into the carousels is segregation of specific medication types. When it is necessary to segregate by route of administration, extra caution should be exercised to avoid placing LASA medications next to one another. Increased grouping of medications based on route of administration makes this exponentially more difficult. If storage by route of administration is a state requirement, it may be prudent to petition your board of pharmacy for an exemption. An excellent case can be made that this type of storage segregation is no longer a necessity and negates many of the positive benefits of the APCS. A second method of segregation is based on the cytotoxicity of the medications. There are advantages to segregating cytotoxic medications, including the ability to semi-automate the auxiliary labeling processes that many institutions do for these items. A simple act like putting the roll of cytotoxic stickers on the shelf/shelves where these medications are stored can serve as a “just in time” reminder to staff and improve labeling compliance.

Before loading the carousel, it also is important to decide what items (if any) will not be loaded into it. Potential “do not load” items include: • Oral and parenteral cytotoxic medications in liquid form (due to spill risk) • Controlled substances (due to regulatory/perpetual inventory concerns) • Large, bulky items (may waste too much valuable carousel space) • Extremely heavy items (check the load-bearing ability of shelves if in doubt)

Loading Carousels Regardless of the approach taken, physically placing medications into the carousel is a time-consuming and challenging process. There probably is no single best approach; however, several potential options are discussed below to help guide the decision-making process.

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see IMPLEMENTATION, page 50

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CLINICALLY RELEVANT SEARCH RESULTS MOST COMPREHENSIVE DRUG INFORMATION CLEAN, UNCLUTTERED INTERFACE

50 Technology

Pharmacy Practice News • October 2009

Robotics Figure 1: Stacked Workload

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Duplicate inventory method. In this approach, new drug stock is purchased to fill the carousel while the existing inventory is used to provide care to patients.

Advantages: minimizes disruption to existing operations; ensures full carousels at the time of conversion to APCS dispensing; ensures individual and bulk packages are available for barcode association.

Disadvantages: significant increase in on-hand inventory that must be carefully managed and budgeted; drugs loaded in the carousel may reflect only the most recently purchased generic equivalents for a particular product; there may not be sufficient space to move the static shelf inventory into the carousel after conversion, resulting in a prolonged transition period.

50% Method. The 50% method involves allocating roughly half of the existing inventory to the carousel, while the remaining items stay on the shelves to support ongoing operations. On conversion day, the remaining inventory is loaded into the carousels as time allows, with a target completion of 48 to 72 hours.

Advantages: eliminates budgetary impact; carousels can be fully used at time of conversion.

Disadvantages: must manually override and correct wholesaler orders so replacement inventory is not ordered prematurely; potential for insufficient quantities of high-velocity items in the old static shelves and in the APCS; very difficult to find the time to relocate remaining inventory in the midst of this major workflow change.

Hybrid method. The hybrid method combines the above options. The duplicate inventory method is used for high-velocity/low-cost inventory items, whereas the 50% method is used for low-velocity/high-cost items. This approach minimizes the disadvantages of the two options, while maximizing their benefits.

Divide and conquer method. In this approach, the inventory is divided into more manageable segments (i.e., 200 inventory lines). During periods when carousel use is low, segments of 200 medications are transferred from static shelving to the APCS. At the time of the next batch or cabinet fill, technicians will pick from both the static shelving items and the APCS. Over the course of a few days, the entire inventory is loaded into the APCS and picking from the static shelves ceases.

Advantages: no extra inventory required; stockouts in the old and new storage locations are minimized; the wholesaler order generated by the

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Place order Patient batch ADC zone pull Processing returns First doses

APCS can be used without significant review or modification; staff can acclimate to the APCS in a more controlled manner.

Disadvantages: geographic location of the static shelves in relation to the carousels may decrease productivity; near the end of the process, it will become more difficult to find APCS “downtime” during which the next segment of 200 medications can be transferred CHN employed the 50% method; however, it took a number of days to move the remaining static shelf inventory into the carousels. In retrospect, given the physical proximity of the hospital’s two inventory locations, the divide and conquer approach would have been ideal.

Stacking Versus Queuing Numerous pharmacy operations are impacted by installation of the APCS. They include order placement; order processing/shelving; ADM restocking; cart/batch fill; first dose dispensing; physical inventory; retrieval of medications for restocking carts/kits/trays; and retrieval of medications for stocking in remote pharmacy locations (satellites, IV room, remote facilities).

In a traditional pharmacy, much of this work can be done simultaneously with minimal difficulty (a stacked

work approach; Figure 1). Installation of carousels requires careful redesign of these tasks into a more sequential pattern (Figure 2). This process ideally should begin before the carousel goes live, but that may not be possible due to limitations with the existing pharmacy design and processes.

The need for sequential workflow can be minimized through three initiatives.

First, workflow should be designed to minimize the amount of time spent at the carousel. For example, verification of bar-code recognition should be performed in the inventory receiving/ breakdown area and not at the carousel.

Second, software configuration should provide flexible, automated management of each of the pharmacy operations listed above. By assigning appropriate priorities to different transaction types, delays in patient care can be minimized and efficiencies maximized.

Finally, larger facilities may want to consider purchasing multiple carousels to handle different functions.

Conclusion Implementation of an APCS touches nearly every aspect of pharmacy operations. Such significant change is unlikely to proceed without some degree of difficulty. However, given the potential safety and efficiency benefits of an

APCS, I believe that the difficulties and challenges are worthwhile.

The author would like to thank the pharmacy staff of Community Hospital North for their patience and support during this project. The impact on pharmacy operations was significant and would not have been successful without the buy-in and assistance of the entire staff. Also, special thanks to Jennifer Mullen, who at the time of our carousel installation was an administrative pharmacy resident with Community Health Network. Her efforts were also critical to the success of this project.

References 1.

Poon EG, Cina JL, Churchill W, et al. Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy. Ann Intern Med. 2006;145:426-434.

2.

Oswald S, Caldwell R. Dispensing error rate after implementation of an automated pharmacy carousel system. Am J Health Syst Pharm. 2007;64:1427-1431.

3.

Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration—2008. Am J Health Syst Pharm. 2009;66:926-946.

4.

Survey on LASA drug name pairs: who knows what’s on your list and the best way to prevent mix-ups?

Nurse Advise-ERR. 2009;7:1-3.

5.

Tuohy N, Paparella S. Look-alike and sound-alike drugs: errors just waiting to happen. J Emerg Nurs.

2005;31:569-71.

6.

Beyea SC. Confusing, look-alike, and sound-alike medications. AORN J. 2007;86:861-863.

Midazolam Hydrochloride Injection CIV Brief Summary See package insert for full prescribing information Adult and Pediatric Intravenous midazolam HCl has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam HCl should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and sizeappropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. (See WARNINGS.) For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure and route dependent (see DOSAGE AND ADMINISTRATION in full prescribing information).

Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION in full prescribing information).

INDICATIONS AND USAGE Midazolam HCl Injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents.

With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY in full prescribing information).

CONTRAINDICATIONS Injectable midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with openangle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Midazolam HCl Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.

WARNINGS Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry.

Hypoventilation, airway obstruction and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY in full prescribing information) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients.

Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION in full prescribing information.

Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY in full prescribing information). Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.

Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established.

Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.

The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously.

The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY in full prescribing information) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

Usage in Pregnancy An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration.

The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources.

PRECAUTIONS General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS above and DOSAGE AND ADMINISTRATION in full prescribing information). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia.

Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.

Use with Other CNS Depressants The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient’s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOX WARNING, WARNINGS above and DOSAGE AND ADMINISTRATION section in full prescribing information.) Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal, see DRUG ABUSE AND DEPENDENCE section.

Drug Interactions The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION in full prescribing information).

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.

These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam.

For additional drug interaction information, refer to full prescribing information.

Pregnancy Teratogenic Effects – Pregnancy Category D (see WARNINGS) Labor and Delivery In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations.

The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use.

Nursing Mothers Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman.

ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, e.g., upper endoscopy and dental procedures.

Adults: The following additional adverse reactions were reported after intramuscular administration: headache (1.3%); Local effects at IM injection site included: pain (3.7%), induration (0.5%), redness (0.5%), muscle stiffness (0.3%).

Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION in full prescribing information).

The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache (1.5%), drowsiness (1.2%); Local effects at the IV site included: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), phlebitis (0.4%).

Pediatric Patients The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see BOX WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections.

DRUG ABUSE AND DEPENDENCE Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970.

Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs.

Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.

Withdrawal symptoms similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient’s needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days.

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Baxter, Committed to a Safer Healthcare Environment, and the distinct product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111198B 09/09